1 Center for Clinical Pharmacology, 3 Department of Medicine, and 4 Department of Pharmacology, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania 15213; and 2 Clinic for Endocrinology, Department of Obstetrics and Gynecology, University Hospital Zurich, 8091 Zurich, Switzerland
![]() |
ABSTRACT |
---|
A number of cellular and biochemical processes are involved in the pathophysiology of glomerular and vascular remodeling, leading to renal and vascular disorders, respectively. Although estradiol protects the renal and cardiovascular systems, the mechanisms involved remain unclear. In this review we provide a discussion of the cellular, biochemical, and molecular mechanisms by which estradiol may exert protective effects on the kidneys and vascular wall. In this regard, we consider the possible role of genomic vs. nongenomic mechanisms and estrogen receptor-dependent vs. estrogen receptor-independent mechanisms in mediating the protective effects of estradiol on the renal and cardiovascular systems.
estradiol; metabolism; methoxyestradiol; hyperplasia; growth factors; antimitogenic; menopause; smooth muscle cells; mesangial cells; endothelial cells
![]() |
INTRODUCTION |
---|
PREMENOPAUSAL WOMEN HAVE A decreased
incidence of cardiovascular disease and a decreased rate of progression
of renal disease. With the onset of menopause, however, decreased
synthesis of 17-estradiol (estradiol) is accompanied by an
increased incidence of cardiovascular disorders and accelerated
progression of renal diseases.
The glomerulus and the vascular wall are not static, and components of these structures dynamically increase, decrease, or reorganize in response to physiological and pathological stimuli. Although multiple cellular and biochemical processes are involved in glomerular and vascular remodeling, glomerular mesangial cells (GMCs) in the kidney and smooth muscle cells (SMCs) in the vasculature are the final common pathway for dynamic changes in glomerular and vascular wall structure. In glomerular and vascular remodeling, GMCs and SMCs undergo one or more of four basic processes: cell growth involving hypertrophy or hyperplasia; cell migration involving the immigration of GMCs or SMCs from one locale to another in the glomerular tuft or vascular wall, respectively; modulation of the amount and types of extracellular matrix (ECM); and apoptosis, which provides an important means of population control for GMCs and SMCs. Glomerular and vascular endothelial cells also play a critical role in maintaining homeostasis by generating a battery of both growth-inhibitory and growth-stimulatory factors, as well as relaxing and contracting factors. Consequently, endothelial damage or dysfunction often leads to increased SMC and GMC migration, proliferation, and ECM synthesis.
Estradiol may induce protective effects on the renal and cardiovascular system by altering SMC, GMC, or endothelial cell biology so as to prevent glomerular and vascular remodeling, and the main purpose of this review is to provide an overview of the participating mechanisms in this regard. A prerequisite for comprehending these mechanisms is an understanding of the processes by which estradiol induces its cellular, biochemical, and molecular effects.
![]() |
CELLULAR AND BIOCHEMICAL EFFECTS OF ESTRADIOL |
---|
Estradiol influences cell growth and differentiation of the male and female reproductive tissues. For example, estradiol regulates the development of mammary glands, uterus, vagina, ovary, testes, epididymis, and prostate (130) and also plays an important role in the vascular system, a system that is essential to reproductive processes. (107, 130, 173, 243). Findings in the last decade indicate that estradiol induces its biological effects via genomic and nongenomic mechanisms and that the effects of estradiol are triggered by estrogen receptor-dependent as well as estrogen receptor-independent mechanisms.
Role of Estrogen Receptors
Estradiol diffuses through the plasma membrane of cells and binds to specific, high-affinity intracellular estrogen receptors (ERs) within the target cell. The nuclear hormone receptor complex binds to chromatin at specific regions of the DNA estrogen response elements (EREs), and this interaction of activated ERs with EREs stimulates or inhibits specific gene expression and protein synthesis.Changes in the generation of intracellular proteins triggers a cascade of events that influences metabolic processes and translates into cell growth and differentiation. It is well documented that estradiol induces uterine growth (hypertrophy and hyperplasia) and the expression of protooncogenes, which may play a role in estradiol-induced cell growth and proliferation (230). In uterine cells, treatment with estradiol rapidly increases the steady-state expression of N-myc, c-myc, c-ras, and c-fos mRNA (230). In addition, ERs increase the synthesis of growth factors such as epidermal growth factor (EGF) and insulin-like growth factor (IGF) and stimulate the levels of growth-promoting peptides that can act in an autocrine fashion to induce cell growth (see reviews in Refs. 230 and 237).
In MCF-7 cell lines, estradiol increases EGF-induced activator protein-1 (AP-1), suggesting that there may be signaling connections between ERs and EGF-induced AP-1 activity (216). Thus estradiol not only induces growth factor synthesis and growth factor receptor synthesis (230) but also facilitates growth factor receptor signal transduction mechanisms. Estradiol, by inducing c-fos, synergies with low concentrations of insulin, which is able to induce c-jun but not c-fos (282). Even when c-fos and c-jun synthesis and AP-1 activity are maximally induced by growth factors, estradiol can still enhance AP-1-dependent transcriptional activity (248). ER mutants lacking the DNA binding domain interact with fos and jun to increase transcription (75). This demonstrates that the ER, a classic DNA binding protein, can act through protein-protein interactions without binding directly to DNA. Consequently, anything that alters the ER to fos or jun ratio will alter the rate of transcription of specific target genes. This observation provides the basis for crosstalk between multiple pathways. Via the above mechanism the AP-1 DNA binding sequence in the chicken ovalbumin gene promoter can be a target for both estradiol activation and cooperation for AP-1 (75). Moreover, in vivo studies in ovariectomized rats show that EGF enhances the nuclear localization of ERs, suggesting that EGF activates the ER to bind to ERE sequences (108).
Recent studies by Kuiper et al. (134) demonstrate that, in
addition to classic ER receptors cloned more than a decade ago (84) and now classified as ER-, cells from rats, mice,
and humans also express another ER, termed ER-
(59, 134, 178, 277). Rat ER-
cDNA encodes a protein of 485 amino acid
residues with a molecular mass of 54,200. In the DNA binding domain,
this ER protein is highly homologous to rat ER-
, with 95% amino
acid identity, whereas in the COOH-terminal ligand binding domain, it
has 55% homology. Similar homologies between ER-
and ER-
have
been found in ERs from mice (215, 277) and humans
(59). ER-
is expressed in prostate, ovary, epididymis,
testis, bladder, uterus, kidney, lung, thymus, colon, small intestine,
blood vessels, pituitary, hypothalamus, cerebellum, and brain cortex
(59, 107, 133, 215, 277).
Whether ER- and ER-
play a similar or different role in mediating
the physiological effects of estradiol is unclear. However, differential expression of ER-
and ER-
is observed in some
tissues (131, 133, 134), which suggests different
physiological roles for these receptors. In this regard, compared with
ER-
, high amounts of ER-
mRNA are in fetal ovaries, testes,
adrenals, and spleen of the midgestational human fetus
(24). Moreover, differential activation by liganded ER-
vs. ER-
occurs at the AP-1 site (208), and
xenoestrogens differentially activate EREs when liganded to ER-
vs. ER-
(213).
In addition to the classic ERs, another ER, termed type II ER,
exists (160). Some ligands for type II ER, such as
bioflavonoids, have no affinity for ER- or ER-
yet abrogate the
effects of estradiol on cell growth (161), suggesting
that, in addition to ER-
and ER-
, the biological effects of
estradiol may be modulated via type II ER. The type II ER may also be
involved in inducing the effects of estradiol in the vasculature and
the kidney.
Apart from the cytosolic/nuclear ERs, estradiol also binds with high affinity to membrane fractions prepared from isolated pituitary and uterine cells (209, 217, 230). The functional role of the membrane receptors for estradiol is evident from the findings that estradiol stimulates adenylyl cyclase activity in membranes prepared from secretory human endometrium (230). Moreover, estradiol induces rapid changes in intracellular calcium levels/flux, K+ conductance, and cAMP levels (9, 183, 217).
Role of Estradiol Metabolism
Several lines of evidence suggest that some of the effects of estradiol may be mediated via its metabolites. Estradiol is eliminated from the body by metabolic conversion by cytochrome P-450 enzymes (CYP450s; 164). Many isoforms of CYP450s exist; however, the isozymes that metabolize steroids such as estradiol are CYP1, CYP2, and CYP3 (164, 307). Although most of the metabolites of estradiol are hormonally less active, water soluble, and excreted in the urine, some of the metabolites have significant growth regulatory effects (see review in Ref. 307). The importance of estradiol metabolism is illustrated by the findings that inhibition of CYP450 enzymes by cimetidine increases estradiol levels and high doses of cimetidine may cause gynecomastia (72).Estradiol is largely metabolized within the liver via oxidative metabolism (to form hydroxylated metabolites such as 2- and 4-hydroxyestradiol) (164); glucuronidation (to form glucuronide conjugates) (307); sulfatase action (to form sulfates) (307); esterase action (to form fatty acid esters) (307); and O-methylation of catechol estradiols (to form O-methylated catechols; 12; for details, see reviews in Refs. 230 and 307).
Even though estradiol is largely metabolized within the liver, cells in several other tissues, including the kidney and the vasculature, contain CYP450 and metabolize estradiol and its metabolites (307). The metabolism of estradiol locally within a tissue may be of immense importance in mediating several of its physiological as well as pathophysiological effects. Several studies provide evidence that the catechol estradiols can induce biological effects, and 2-hydroxyestradiol is a weak ligand for ER and may regulate multiple mechanisms in reproductive tissues, including growth of cancer cells and generation of prostaglandins in the uterus during pregnancy (12, 230, 307). 2-Hydroxyestradiol attenuates catabolism of catecholamines by inhibiting catechol O-methyltransferase activity, and this may modulate the neurophysiological and pharmacological effects of catecholamines within the kidneys and vasculature (12, 230, 307). 2-Hydroxyestradiol also modulates the interaction of dopamine with its receptors (230, 307). Additionally, 2-hydroxyestradiol is a potent antioxidant and thereby protects membrane phospholipids and cells against peroxidation (56).
Similar to 2-hydroxyestradiol, 4-hydroxyestradiol induces several important biological effects. Even though it is not the dominant metabolite formed by the liver, 4-hydroxyestradiol is a major metabolite formed in some extrahepatic tissues such as rat pituitary and human myometrial, myoma, and breast tissue, as well as kidney and vasculature tissue (307). In contrast to estradiol, 4-hydroxyestradiol binds with low affinity to ER; however, its dissociation rate from the receptor is much lower than that observed for estradiol (230). Within the renal system, 4-hydroxyestradiol has been shown to stimulate tumor growth in Syrian hamsters (307) and uterotrophic effects in rats (164, 225). 4-Hydroxyestradiol is more efficacious than estradiol in inducing progesterone receptor expression in the rat pituitary (230). Similar to 2-hydroxyestradiol, 4-hydroxyestradiol also acts as a cooxidant and increases the formation of prostaglandins from arachidonic acid within the uterus during pregnancy (230). 4-Hydroxyestradiol prevents inactivation of catecholamines by inhibiting catechol O-methyltransferase activity and thereby regulates the neuropsychological/pharmacological effects of catecholamines on the central nervous system (230, 307).
In contrast to 2-hydroxyestradiol, 4-hydroxyestradiol induces carcinogenic effects (230, 307). In fact, recent studies provide evidence for reduced 2-hydroxylation and increased 4-hydroxylation of estradiol in subjects with cancer, suggesting that 2-hydroxyestradiol or its methylated metabolite (2-methoxyestradiol) may be anticarcinogenic, whereas 4-hydroxyestradiol and its metabolite 4-methoxyestradiol may be carcinogenic (148, 230, 307). Because abnormal growth of cells is a hallmark for both atherosclerosis, glomerulosclerosis, and cancer, it is feasible that the catechol metabolites of estradiol may also play an important role in regulating cell growth within the vessel wall and the glomeruli.
Role of Binding Proteins
The effects of estradiol can also be influenced by factors regulating its transport to target tissues. In this regard, estradiol is known to bind to serum hormone-binding globulin (SHBG), the synthesis of which is influenced by other hormones (103). The unbound fraction of estradiol is important for inducing its biological activity; moreover, the extent of binding also influences the rate of estradiol metabolism and its elimination from the body, thereby influencing its half-life and pharmacological effects. Hence, any factors that influence the levels of SHBG will subsequently influence the biological effects/activity of estradiol. Within the circulation, 40% of estradiol is bound to SHBG, and the levels of SHBG are influenced by estrogens (increased; 103, 230); androgens (decreased; 103); progestins (decreased; 103); and pathological conditions such as polycystic ovarian syndrome (103). Apart from SHBG, estradiol can also bind to albumin and other membrane proteins (103), which may also influence its biological effects.Some metabolites of estradiol, e.g., 2- and 4-methoxyestradiol, have low binding affinity to classic ERs but have a higher binding affinity to SHBG than estradiol (230, 307). This suggests that the methoxy metabolites of estradiol may have a longer half-life and may be present within the circulation at much higher levels.
Role of Aryl Hydrocarbon Receptors in Regulating the Biological Effects of Estradiol
The aryl hydrocarbon receptor (AhR) may play a critical role in influencing the effects of estradiol. The unoccupied AhR is a helix-loop-helix (HLH) protein localized within the cytosolic compartment of cells and is a member of the HLH superfamily of proteins, which includes AhR nuclear translocator protein (ARNT); the Dorsophila proteins, single minded and period; as well as hypoxia-inducible factor-1The inactive cytosolic AhR is found complexed with two heat shock
protein 90 (hsp90) molecules and a 43-kDa protein (p43). Binding of
halogenated aromatic hydrocarbons and environmental estrogens to the
AhR initiates disassociation of the hsp90 and p43 molecules and
formation of an AhR-ARNT dimer (231). The liganded AhR-ARNT complex is active, translocates to the nucleus, binds to DNA
at xenobiotic regulatory elements, and induces the expression of
several genes including CYP450 (231, 242). Because CYP450 is involved in estradiol metabolism, the activation of AhR results in
increased metabolism of estradiol and influences its biological activity. Moreover, the profile of estradiol metabolites is influenced depending on the types of CYP450 isozymes induced. In MCF-7 cell lines,
ligand-activated AhR induces CYP1A1 activity and estradiol metabolism
via increases in oxidative metabolism by activating 2- and
4-hydroxylation as well as the 15- and 16
-hydroxylases (230), suggesting that AhR may influence the biological
effects of estradiol by increasing its metabolism.
Crosstalk between ERs and AhRs may also play a role in modulating the effects of estradiol (230, 237). In both MCF-7 and T47D cell lines, ligand-induced activation of AhR inhibits several ER-induced responses. In this regard, AhR decreases ER-induced secretion/production of tissue plasminogen activator (230, 237), postconfluent focus proteins (230, 237), 52- and 160-kDa proteins (237), cathepsin D mRNA, cathepsin D protein (237), pS2 mRNA (237), progesterone receptors and progesterone receptor mRNA levels (230). Moreover, AhR activation alters ER-induced changes in cell proliferation (237) and glycolysis (230, 237). Also, AhR activation downregulates ER mRNA and protein. Safe (237) proposes additional mechanisms via which ligand-activated AhR may induce antiestrogenic effects including interactions between AhR and the ER-induced pathways via generation of intermediary metabolites; direct interactions between the nuclear AhR and the cis-acting genomic sequences in the promoter regions of ER-regulated or growth factor-regulated genes; and induction of trans-acting factors or proteins that facilitate degradation of the nuclear ER (for details, see reviews in Refs. 230, 231, 237).
![]() |
VASOPROTECTIVE EFFECTS OF ESTRADIOL: ROLE OF GENOMIC VS. NONGENOMIC AND RECEPTOR VS. NONRECEPTOR MECHANISMS |
---|
Estradiol most likely induces vasoprotective effects; however, the mechanisms by which these effects are induced remain unclear. Alterations in plasma concentrations of lipoproteins [decrease in low-density lipoprotein (LDL) levels, decrease in oxidized LDL formation, increase in high-density lipoprotein (HDL) levels], hemostatic factors, glucose, insulin, and endothelium-derived factors (decrease in endothelin, increase in nitric oxide and prostaglandins) and inhibition of smooth muscle cell migration and proliferation induced by various mitogens [i.e., platelet-derived growth factor (PDGF), basic fibroblast growth factor (bFGF), insulin-like growth factor I (IGF-I), and ANG II] are hypothesized to contribute to the vasoprotective effects of estradiol (62, 67, 166, 203, 229). Regardless of the mechanisms, the two most important effects of estradiol in the cardiovascular system are modulation of vascular tone and inhibition of vascular growth.
Effects on Vascular Tone
Estradiol induces vasodilatory effects on the vasculature within minutes, suggesting that its vasodilatory effects are nongenomic in nature. In this regard, acute administration of estradiol ex vivo and in vivo induces a rapid vasodilatation in coronary arteries of cholesterol-fed ovarectomized primates and other animals (62, 166, 267, 298). In humans, estradiol dilates coronary and brachial arteries in postmenopausal women and in men (38, 80, 87, 222). Moreover, in vitro studies with isolated vessels provide convincing evidence that estradiol can acutely induce vasodilatory effects (295, 297).The acute vasodilatory effect of estradiol is largely mediated via
generation of nitric oxide (NO) because the vasodilatory effect of
estradiol is blocked by NO synthesis inhibitors (31, 35,
139). Estradiol also enhances NO synthesis in endothelium denuded rat aorta (20). Evidence for the role of ERs in
mediating the effect of estradiol on NO synthesis comes from the
findings that the vasodilatory effect of estradiol and the effect of
estradiol on NO synthesis by endothelial cells are blocked by
ICI-182780 (31, 35), an ER antagonist. With regard to the
role of ER- and ER-
in regulating NO synthesis, studies show that
compared with wild-type mice, estradiol-induced NO synthesis and
relaxation of the aorta are reduced in mice lacking ER-
(232). Moreover, increased endothelial-derived nitric
oxide synthase (eNOS) activation in response to estradiol is observed
in endothelial cells overexpressing ER-
(35).
Additionally, a significant association between the number of ERs and
basal release of NO is observed in ER-
-knockout mice
(232); however, there was no correlation between NO
release and estradiol levels. These findings suggest that the effects on NO synthesis are ER-
mediated. The fact that these effects are
triggered within 5 min suggests that the effects are nongenomic (262) and that NO plays a major role in mediating the
acute vasodilatory effects of estradiol. This notion is further
supported by the observation that estradiol-induced activation of eNOS
is not abrogated by actinomycin D (35).
The mechanisms by which estradiol induces the rapid increase in NO
release from endothelial cells are unclear and under debate. Recent
findings suggest the involvement of calcium-dependent translocation of
eNOS from cell membrane to the nucleus (81). NO release by estradiol may involve a plasma membrane rather than a nuclear ER
(123). Plasmalemmal caveolae possess ER
(123), eNOS, and caveolin; plasma
membrane-impermeable BSA-conjugated estradiol stimulates NO
release; and the effects of estradiol on NO release are blocked by
agents that decrease intracellular calcium and by the ER antagonist
ICI-182780 (123). Recent studies demonstrate ER- in
endothelial cell membranes, and this membrane receptor induces acute
effects on NO synthesis (235). Although, the above findings and vast majority of studies suggest a role of intracellular calcium in regulating the rapid release of NO in response to estradiol, this conclusion is not supported by one study (31). Other
mechanisms that may be involved are activation of tyrosine kinase and
mitogen-activated protein kinase pathways because inhibitors for these
pathways block the effects of estradiol on NO production (35,
168). It is proposed that the nongenomic stimulation of NO
synthesis may involve intracellular proteins, such as hsp90, which is
known to bind to and activate eNOS and may interact with ERs
(168). Estradiol upregulates the expression of hsp25 in
endothelial cells (45). Alternatively, the antioxidant
effects of estradiol may potentiate the activity of NO released under
basal conditions. In this regard, estradiol increases rat aorta
endothelium-dependent relaxing factor (EDRF) activity in the absence of
changes in eNOS gene expression and this increase in EDRF is associated
with decreased generation of O
in response to
estradiol and could account for the enhanced EDRF-NO bioactivity and
decreased peroxynitrite release (13, 55)
The role of NO in mediating the acute, nongenomic vasodilatory effects of estradiol is well established. Even so, other mechanisms may also mediate estradiol-induced vasodilation. In this regard, membrane fluidity and ion-channel activity (e.g., Maxi-K and voltage-dependent L-type calcium channels) may play an important role. Application of estradiol stimulates rapid discharge of transient outward currents and induces an increase in the intracellular free calcium concentration in endothelial cells (234). Estradiol also causes coronary vasodilation by opening calcium-activated K+ channels (200) and relaxes endothelium-denuded porcine coronary arteries by opening large-conductance (BKCa), calcium-activated, and voltage-activated K+ channels via NO and cGMP (44). Estradiol inhibits voltage-dependent L-type calcium currents in SMCs (186) and induces potent stimulatory effects on large-conductance, calcium-activated, and voltage-activated K+ channels in coronary artery SMCs. Because the vasodilatory effects of estradiol in intact arteries is abrogated by BKCa channel blockers and inhibitors of cGMP-dependent protein kinase, it is feasible that estradiol induces its vasodilatory effects by opening BKCa channels via NO and cGMP-dependent pathways (295, 297).
Although the role of ERs in mediating the effects of estradiol on ion
channels has not been intensively investigated, findings from some
studies provide evidence that they may not participate in the process.
The inhibitory effects of supraphysiological concentrations (>100 nM)
of estradiol on L-type calcium channels are mimicked by the ER
antagonist ICI-182780 (233). Moreover, in
endothelium-denuded vessels, attenuation of high-K+-induced
force development and myosin light chain phosphorylation are not
blocked by an ER antagonist and are mimicked by estradiol analogs with
negligible affinity for ERs (126). Interestingly, recent
studies demonstrate that at concentrations of >100 nM (pharmacological concentration) estradiol binds to the -subunit of Maxi-K channels in
vascular SMCs and induces Maxi-K channel activation. This finding provides the first evidence that the direct interaction of estradiol with a voltage-gated channel subunit may be responsible for the direct
and acute relaxing effects of estradiol on SMCs (280).
Estradiol rapidly activates adenylyl cyclase activity and increases cAMP production (52, 61). Moreover, via the cAMP-adenosine pathway, estradiol induces the production of adenosine in vascular SMCs (52). The fact that the effects of estradiol on cAMP and adenosine synthesis are blocked by an ER antagonist, but not by cyclohexamide, suggests that these effects are mediated via nongenomic, but ER-linked, mechanisms. Because adenylyl cyclase is a membrane-bound enzyme, it is feasible that estradiol may directly interact with adenylyl cyclase. Alternatively, activation of ion channels (as discussed above) may be responsible for the stimulatory effects of estradiol on adenylyl cyclase. Additional studies are required to elucidate the mechanisms by which estradiol induces cAMP and adenosine synthesis.
Although the above findings provide evidence that estradiol induces cAMP production, whether these effects are induced by physiological concentrations of estradiol remains unresolved. In this regard, some studies (37) show that physiological concentrations of estradiol are unable to induce significant increases in cAMP production. However, studies from our laboratory provide evidence that the effects of physiological concentrations of estradiol are significantly blocked by the adenylyl cyclase inhibitor dideoxyadenosine, suggesting that physiological concentrations of estradiol are capable of stimulating cAMP production (52).
Finally, in addition to the above pathways, other mechanisms may also be responsible for the acute nongenomic effects of estradiol on the vasculature. For instance, because estradiol is a phenol, it may induce antioxidant effects and protect the vasculature from free radical-induced deleterious effects.
The rapid-onset, nongenomic effects of estradiol may play an important
role in regulating vascular tone; however, the long-term genomic
effects of estradiol also importantly contribute to the vascular
protective effects of estradiol. Long-term treatment with estradiol
induces eNOS (294) and abrogates vasoconstrictor effects
on vascular tissues (39, 122, 232). Compared with premenopausal women, NO synthesis is decreased in postmenopausal women
and is normalized by estradiol replacement therapy (110, 228). This effect of estradiol replacement therapy, however, is
diminished by coadministration of synthetic progestin,
medroxyprogesterone, and cyproterone acetate (110).
Vascular NO synthesis is decreased in mice lacking ER-
(232), and long-term administration of estradiol increases
acetylcholine-mediated coronary vasodilation in nonhuman primates
(298, 299), male-to-female transsexuals
(197), postmenopausal women (95), and in
postmenopausal women with angina and normal coronary arteries
(224). The role of genomic effects of estradiol on
vascular tone is further supported by the recent observation that
impaired endothelium-dependent vasorelaxation (267) and early coronary calcification (266) are observed in a
subject lacking functional ER-
. However, the vasodilatory response
to estradiol was adequate, suggesting a nongenomic response and that a
lack of ER-
may not be as deleterious as previously hypothesized (266, 267). Indeed, estradiol prevents neointima formation
in ER-
-knockout mice (107). Estradiol also increases
the synthesis of prostacyclin by inducing the expression of
prostacyclin synthase (33, 169) and cyclooxygenase
(115).
Estradiol reduces blood pressure in various animal models (26, 43, 142, 249), and the modulatory effects of estradiol on vascular tone may be responsible for estradiol-induced effects on blood pressure. Multiple clinical studies show that both long-term and short-term administration of estradiol replacement therapy is associated with either the lowering of blood pressure (92) or blood pressure-neutral effects (275) in most postmenopausal women. However, estradiol replacement therapy infrequently increases blood pressure in postmenopausal women (152). The blood pressure-lowering effect of estradiol may be mediated by direct effects of estradiol on ion channel activity or increased synthesis of vasodilatory substances such as NO, cGMP, cAMP, adenosine, and prostacyclin. Alternatively, estradiol may lower blood pressure by reducing the synthesis of ANG II and endothelin-1 (ET-1) or by interfering with the synthesis of and decreasing the plasma levels of catecholamines (150, 212, 244).
Effects on Vascular Growth
In vivo studies conducted in several animal species and using various models [balloon injury-induced neointima formation, allograft-induced dysplasia, cholesterol/lipid-induced atherosclerosis, and vascular narrowing-induced neointima formation (23, 34, 36, 65, 66, 68, 88, 107, 144, 153, 179, 204, 238, 270)] provide evidence that estradiol prevents pathological vascular remodeling processes and neointima formation. Yet, the exact mechanisms involved remain unclear. Evidence suggests that the inhibitory effects of estradiol on vascular remodeling processes leading to occlusive disorders are mediated via multiple pathways, involving interactions with a variety of growth factors, cell types, and biochemical/molecular mechanisms (62, 67, 166, 203). These mechanisms are discussed below.Interactions with SMCs. Abnormal activity of SMCs is one of the key processes responsible for vascular pathology. In this regard, estradiol inhibits SMC proliferation, migration and extracellular matrix (collagen) synthesis induced by serum, PDGF, ANG II, ET-1, fibronectin, free radicals, IGF-1, bFGF, oxidized-LDL, and mechanical pulsatile stretch (122, 132, 156, 203, 205, 229).
Our recent study provides evidence that estradiol inhibits PDGF-BB-induced growth and mitogen-activated protein (MAP) kinase activity in human aortic SMCs (49, 230). Estradiol also inhibits FCS, ANG II, and ET-1-induced MAP kinase and MAP kinase kinase activity in vascular SMCs (176) and downregulates mitogen-induced expression of both c-myc and c-fos (176), which are known to be activated downstream from MAP kinase. Although estradiol induces its antimitogenic effects on SMCs in part by inhibiting the MAP kinase pathway, other mechanisms are operative. For instance, estradiol inhibits the mitogenic effects of IGF-1 (156), which acts by stimulating phosphatidylinositol turnover, diacylglycerol formation, intracellular calcium flux (22), and protein kinase C (PKC) activity (55). Moreover, estradiol downregulates the expression of IGF-1 receptors in SMCs (156), thus providing another mechanism by which estradiol abrogates the mitogenic effects of IGF. Also, estradiol inhibits transplant arteriosclerosis in the rat aorta accelerated by topical exposure to IGF-1 (179). Because the mitogenic effects of IGF-1 and bFGF on SMC are associated with activation of PKC (55, 290), it is feasible that the inhibitory effects of estradiol are in part mediated via downregulation of PKC activity; however, direct evidence in this regard is lacking. Estradiol stimulates the synthesis of growth inhibitory molecules in SMCs such as cAMP (52, 61). Data from our laboratory provide evidence that estradiol enhances the synthesis of adenosine in SMCs via the cAMP-adenosine pathway, which involves the conversion of cAMP to adenosine via sequential action of ectophosphodiesterase and ecto-5'-nucleotidase at the surface of SMC membranes (52, 55). Because the cAMP-adenosine pathway induces inhibitory effects on SMC growth (55), the antimitogenic effects of estradiol may be mediated in part via this mechanism. Indeed, our studies show that the inhibitory effects of estradiol on serum-induced growth of aortic SMCs are significantly reversed by the adenylyl cyclase inhibitor dideoxyadenosine and by the A2 adenosine-receptor antagonists 1,3-dipropyl-8-p-sulfophenylxanthine and KF-17837 but not by the cAMP-dependent protein kinase inhibitor Rp-cAMPS (52). Moreover, the inhibitory effects of estradiol are associated with increased production of cAMP and adenosine, an effect that is blocked by the ER antagonist ICI-182780 but not by cyclohexamide (52). These findings provide evidence that the inhibitory effects of estradiol mediated via the cAMP-adenosine pathway involve the participation of a nongenomic pathway linked to ERs. Estradiol also upregulates NO synthesis, and NO inhibits SMC proliferation and migration (49, 52, 74). Hence, it is feasible that increased production of NO may also contribute to the inhibitory effects of estradiol on SMC growth. A significant reduction in the antiatherogenic effect of estradiol was observed after long-term inhibition of NO synthesis in cholesterol-clamped rabbits (100). However, inhibition of NO synthesis did not abrogate the protective effects of estradiol in apolipoprotein-deficient mice (58) or cholesterol-induced atherosclerosis in rabbits (189). Thus, although estradiol-induced NO synthesis may participate in mediating inhibition of vascular SMC biology, other mechanism are also involved. Estradiol also inhibits migration of SMCs induced by fibronectin via ER-linked genomic pathways (129). Moreover, via ER-dependent mechanism estradiol enhances the release of matrix-metalloproteinase-2 (a regulator of cell migration) in SMCs (300). Estradiol inhibits mitogen-induced synthesis of elastin and various types of collagen, including types I and III (17, 64). Because collagen is known to induce SMC migration, this mechanism may contribute to estradiol-induced inhibition of SMC migration. The influence of estradiol on generation of inhibitory extracellular molecules or downregulation of the generation of stimulatory molecules from SMCs is supported by the recent findings of Li et al. (145). These investigators demonstrate that, in contrast to conditioned medium obtained from untreated SMCs, conditioned medium from estradiol-treated SMCs inhibits mitogen- as well as SMC- induced migration of adventitial fibroblasts (145). Importantly, conditioned medium obtained from SMCs treated with estradiol plus ICI-182780 does not inhibit fibroblast migration. Because adventitial fibroblasts participate in the vascular remodeling process associated with coronary artery disease, it is feasible that estradiol may directly prevent neointimal thickening by interacting with SMCs to stimulate or inhibit the synthesis of factors that affect the migration of advential fibroblasts.Interactions with endothelial cell, macrophages, and monocytes. Interactions of estradiol with endothelial cells, macrophages, and monocytes may contribute to the vasoprotective effects of estradiol. Under normal circumstances, the endothelium is thought to induce a net inhibitory effect on SMC growth (55), and damage or dysfunction of the endothelium by balloon catheters, vascular cuffs, and immune reactions results in abnormal proliferation of SMCs and neointima formation, effects that are abrogated by estradiol (23, 34, 36, 65, 66, 68, 88, 107, 144, 153, 179, 204, 238, 270).
Estradiol regulates the angiogenesis process by inducing endothelial cell growth in multiple reproductive organs (173); moreover, estradiol accelerates functional endothelial recovery after arterial injury (132). Although the growth-promoting effects of estradiol on endothelial cells are regulated by multiple factors, vascular endothelial growth factor (VEGF) and bFGF appear to play a key role in mediating the mitogenic effects of estradiol on endothelial cells. In aortic endothelial cells estradiol increases bFGF production via a PKC- and ER-dependent mechanism that is nongenomic (5). Moreover, studies show that estradiol induces delayed mitogenesis in human umbilical vein endothelial cells via activation of extracellular signal-regulated kinase 1/2 and that these effects are blocked by antibodies to bFGF (124). These findings suggest that the mitogenic effects of estradiol on endothelial cells may be bFGF mediated. Aortic intimal hyperplasia in ovarectomized sheep is associated with a twofold increase in bFGF levels, and this effect is abrogated in sheep receiving estradiol replacement (247). The fact that bFGF is a mitogen for SMCs and neointima formation occurs in ovarectomized sheep without endothelial damage suggests that the antimitogenic effects of estradiol may rely more on blocking bFGF-induced SMC growth than on stimulating bFGF-induced endothelial cell growth. Additionally, in endothelium injury- or transplant-induced intimal dysplasia, the effects of bFGF on SMC growth may be enhanced as cell injury results in the release of bFGF and NO [generated in response to cytokines via inducible nitric oxide synthase (iNOS); see review in Ref. 55], and in combination with NO the mitogenic effects of bFGF are known to be enhanced severalfold (55). Because estradiol inhibits iNOS activity (121), this would block the synergistic interaction between NO and bFGF. Estradiol may differentially regulate the growth effects of bFGF in SMC and EC (55). Indeed, estradiol inhibits mitogen-induced MAP kinase and MAP kinase kinase activity in SMCs (176) and induces MAP kinase activity in ECs (177, 196). A possible cause for these different effects may be due to the expression of heterogeneous forms of the cognate receptors (97). Alternatively, differential generation of corepressor or coactivator proteins, which bind to steroid hormone receptors and silence the transcription process (172, 251), may contribute to the observed differential effects. VEGF is another important factor that induces endothelial cell growth. Both ECs and SMCs synthesize VEGF, and estradiol induces the synthesis of VEGF in endothelial cells (272). In vivo studies provide evidence that infusion of VEGF after balloon injury results in rapid recovery of the endothelium and inhibition of neointima formation (10, 293), suggesting that VEGF may protect against vasoocclusive disorders. This notion is further supported by the fact that transfer of the VEGF gene reduces intimal thickening in cuff-induced neointima formation in the presence of intact endothelium (138). The mechanism by which VEGF prevents neointima formation is unclear; however, studies show that inhibition of neointima formation in animals with VEGF gene transfer is reversed by the NO synthesis inhibitor nitro-L-arginine methyl ester, suggesting that NO may be the ultimate mediator of the antimitogenic effects of VEGF on SMCs (138). Although estradiol may induce antimitogenic effects on SMCs via VEGF-induced NO synthesis, the role of NO in mediating the inhibitory effects on neointima formation is not supported by all studies. In this regard, protective effects of estradiol on cuff- as well as diet-induced vascular remodeling and neointima formation are not abolished by NO synthesis inhibitors in some studies (58, 100, 189). Moreover, the role of prostanoids can be ruled out as indomethacin does not abrogate the antimitogenic effects of estradiol (4). Hence, other mechanisms than endothelium-derived NO and prostacyclin generation may be involved in mediating the antimitogenic effects of estradiol on SMCs. VEGF induces its mitogenic effects on ECs via activation of a Raf-MEK-MAP kinase-PKC-dependent pathway (273). Because estradiol induces MAP kinase activity in ECs, it is feasible that the effects of estradiol on EC growth and VEGF synthesis are MAP kinase mediated. Estradiol not only induces the synthesis of VEGF but also increases the synthesis and expression of VEGF receptor-2 in endothelial cells (272). Although ER and VEGF mediate the mitogenic effects of estrogen on ECs, however, the role of ER-Modulation of circulating growth factors. Estradiol also induces antivasoocclusive effects by modulating the synthesis of circulating factors that are mitogenic for SMCs and damaging to ECs. In this regard, estradiol downregulates the expression of angiotensin-converting enzyme (ACE) in serum as well as in the aorta and reduces ANG II formation (71). ACE expression is increased at sites of balloon injury and angioplasty (63), ANG II is a potent mitogen for SMCs (49, 54), and ANG II is known to induce vascular remodeling processes associated with cardiovascular disease. The finding that estradiol downregulates ACE and reduces ANG II synthesis suggests that estradiol may abrogate SMC growth in part by decreasing ANG II biosynthesis. Estradiol replacement therapy decreases ANG II levels and ACE activity in postmenopausal women (218) and suppresses renin levels (244). Estradiol also downregulates the expression of AT1 receptors in SMCs (198). Because these receptors mediate the mitogenic effects of ANG II, estradiol may abrogate the effects of ANG II on growth. Indeed, our studies show that estradiol inhibits ANG II-induced growth of human SMCs in vitro (229). Additionally, estradiol induces the synthesis of ANG 1-7, a vasodilator and SMC growth inhibitor (55).
Another important molecule associated with vasoocclusive disorders is homocysteine. It is well documented that homocysteine induces endothelial cell damage (287), inhibits endothelial cell growth, and induces SMC growth (278). Clinical studies provide evidence that estradiol reduces circulating levels of homocysteine in postmenopausal women. In female-to-male transexuals, homocysteine levels increase with androgen treatment, whereas in male-to-female transexuals homocysteine levels decrease with estradiol substitution (283). Compared with women and male-to-female transsexuals, an increased incidence of cardiovascular disease is observed in men as well as in female-to-male transsexuals (79). It is feasible that by lowering homocysteine levels, estradiol protects the vascular endothelium and SMCs from damage and growth, respectively, and this inhibits the remodeling process and protects against vasoocclusive disorders. Another mechanism by which estradiol may induce antivasoocclusive actions is via upregulation of leukemia inhibitory factor (LIF), a factor that inhibits cuff injury-induced neointima formation (175) and hypercholesterolemia-induced fatty streak formation (174) as well as upregulates LDL receptors and lowers serum cholesterol levels (174). This notion is supported by our finding that estradiol can upregulate LIF synthesis in reproductive tissue (221). However, further studies are required to determine whether estradiol-induces LIF synthesis in vascular tissue. Estradiol inhibits serum and ANG II-stimulated synthesis and mRNA expression of ET-1 (177) in endothelial cells via ER receptor-dependent mechanisms (3). Estradiol also blocks the mitogenic effects of ET-1 on SMCs and inhibits ET-1-induced MAP kinase activation (176). Compared with premenopausal women, ET-1 levels are increased in postmenopausal women not taking estradiol, and ET-1 levels are reduced in postmenopausal women after estradiol substitution (304). Estradiol also influences the synthesis of factors associated with coagulation, atherogenesis, and neointima formation. In this regard, estradiol decreases plasma concentrations of procoagulant factors such as clottable fibrinogen (77, 128), soluble thrombomodulin, plasminogen activator inhibitor 1 (128), antithrombin III, and protein S (78, 184, 275). Moreover, most (91), but not all (184, 241), studies report that estradiol decreases levels of von Willebrand factor. It is important to note that the effects of estradiol on coagulation and fibrinolytic factors depend on the type of estrogen used. For example, compared with estradiol, ethinyl estradiol, an oral contraceptive, has different effects on factors involved in regulating coagulation (94). Finally, estradiol stimulates NO (35, 139) and prostacyclin synthesis (33), factors well known to prevent platelet aggregation and adhesion and to induce antimitogenic effects on SMCs. Indeed, the antiaggregatory effects of estradiol can be blocked by NO synthesis inhibitors (187), suggesting that the antiaggregatory effects are NO mediated. In contrast, Zoja et al. (308) demonstrated that estradiol corrects platelet dysfunction in uremia by inhibiting NO and that estradiol has a procoagulant role in patients with chronic renal disease (308).Antioxidant effects. The antioxidant effects of estradiol and its metabolites may play a critical role in the antivasoocclusive effects of estradiol. Indeed, physiological and supraphysiological concentrations of estradiol induce antioxidant activity in vitro and ex vivo/in vivo, respectively (245, 252), and estradiol inhibits oxidized-LDL-induced endothelial damage (191) and superoxide anion (30)- and cholesterol-induced SMC growth (99). We recently demonstrated that physiological concentrations of 2-hydroxyestradiol, a prominent estradiol metabolite, is a potent antioxidant that prevents peroxyl radical-induced peroxidation of vascular SMC membrane phospholipids and inhibits peroxyl radical-induced proliferation and migration of SMCs (56). 2-Hydroxyestradiol prevents the oxidation of acidic membrane phospholipids (phosphatidylinositol and phosphatidylserine), which are known to activate PKC activity and play a critical role in regulating SMC growth (56). Makides et al. (162) demonstrate that methoxy metabolites of estradiol are also potent antioxidants. Because SMCs rapidly convert 2-hydroxyestradiol to 2-methoxyestradiols (53a), it is feasible that the antioxidant effects of 2-hydroxyestradiol on membrane lipids are mediated by methoxyestradiol. Estradiol also reduces glycooxidative damage in the artery wall (288), suggesting that the antioxidant effects of estradiol and its metabolites at the cell membrane level may play a critical role in mediating the growth regulatory and antimitogenic effects of estradiol. Finally however, even though multiple in vitro and ex vivo studies support the notion that estrogen increases the resistance of LDL to oxidation, ample studies in postmenopausal women receiving estrogen show no difference (see review in Ref. 245). Taken together, the evidence for in vivo antioxidant effects of physiological concentrations of estrogen remains controversial.
Interaction with lipids.
Estradiol influences the vascular effects of LDL cholesterol.
Estradiol, which is a phenol with antioxidant properties, prevents the
oxidation of LDL and very-low-density lipoprotein (VLDL) to oxidized
LDL and oxidized VLDL, both in vivo and in vitro (163, 223,
236) and protects the vasculature against the deleterious effects of oxidized lipids. Estradiol also prevents compromise of the
endothelial barrier mediated by LDL and attenuates the accumulation of
LDL and oxidized LDL in the artery wall (73). Also,
TNF--mediated oxidation and accumulation of LDL in the artery wall
are prevented by estradiol (288). Moreover, estradiol increases the catabolism of LDL, LDL apolipoprotein (B), and
-VLDL via LDL receptor-dependent and -independent mechanisms (41, 46). In this regard, estradiol has been shown to increase the expression of LDL receptors (46). Pharmacological levels
of estradiol increase hepatic mRNA for the LDL receptor (18, 96, 259) and increase the synthesis of LDL receptor protein out of proportion to the increase in hepatic LDL receptor mRNA, indicating both transcriptional and posttranscriptional regulation of the LDL
receptor by estradiol (18). Estradiol also improves the clearance of VLDL, decreases LDL production (302), reduces
LDL particle size, increases the clearance of both the light and dense LDL (27), increases expression of VLDL and LDL receptors
in the left ventricles of the heart (48, 165), and induces
sterol-27-hydroxylase activity, which decreases LDL production
(136). Estradiol-induced removal of VLDL is associated
with increased activities of hepatic lipase, lipoprotein lipase, and
expression of LDL receptors (46). There is also evidence
for crosstalk between ERs and LDL receptors and for upregulation of ER
associated with an increase in LDL receptor expression, and these
effects can be blocked by the ER antagonist tamoxifen
(210).
Evidence for non-receptor-mediated antimitogenic effects of
estradiol.
Vascular ECs and SMCs express the functional ERs, ER- and ER-
(98, 262). However, whether the cardiovascular effects of
estradiol are ER mediated is still unresolved and under debate. Recent
studies by Isfrati et al. (107) show that estradiol
induces vasoprotective effects in mice lacking ER-
, suggesting that
the effects may be mediated via ER-
. The notion that ER-
mediates antivasoocclusive effects of estradiol is further supported by the
finding that, similar to estradiol, low concentrations (25 µg · kg
1 · day
1) of
genistein, a phytoestrogen that binds exclusively to ER-
and has
negligible affinity for ER-
binding (135),
inhibits balloon injury-induced neointima formation (157).
However, this study does not provide any evidence regarding whether the
effects of genistein are blocked by ER antagonists such as ICI-182780; moreover, inhibitory effects of genistein on SMC growth are observed at
concentrations of >2.5 µM. Hence it is feasible that the effects of
genistein are mediated via some alternative pathway not involving ERs.
Indeed, at micromolar concentrations genistein is a tyrosine kinase
inhibitor and inhibits growth of cancer cells containing or lacking ERs
(292). Moreover, our previous study demonstrates that the
inhibitory effects of genistein on human aortic SMCs are not reversed
by ICI-182780 (50). Also, Karas et al. (118) provide evidence that estradiol protects against vascular injury in
mice in which ER-
is genetically disrupted. Together, these finding
provide evidence that estradiol can induce vasoprotective effects via
mechanisms independent of ERs. However, the possibility that the ER-
may compensate for ER-
in ER-
-knockout mice, and vice versa,
remains an unresolved issue. In a recent study, Bakir et al.
(11) demonstrated that the inhibitory effects of estradiol on neointima formation are blocked by ICI-1827980, suggesting that the
effects are ER mediated. However, the authors also observed that
concentrations of ICI-182780 that blocked the effects of estradiol also
induced circulating levels of estradiol (11). Because
estradiol metabolites are more potent than estradiol in inhibiting SMC
growth and ICI-182780 inhibits estradiol metabolism (53a),
it is feasible that the effects of ICI-182780 may be due to
inhibition of metabolism of estradiol and not to the antagonistic effects on ERs.
![]() |
ENDOGENOUS ESTROGEN: BIOLOGICAL POTENCY AND PATHOPHYSIOLOGICAL IMPORTANCE |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
In addition to estradiol, numerous other estrogens are present in vivo and are known to possess biological activities that are similar to estradiol as well as activity that is opposite to estradiol. Hence, the effects of estradiol may not reflect the effects of all estrogens. Conversely, the effects of other estrogens may not reflect the biological effects of estradiol. Our recent studies show that the inhibitory effects of various estrogens on mitogen-induced SMC growth and MAP kinase activity vary considerably. Estrone and estriol, which are present in large amounts endogenously, are not effective in inhibiting SMC growth and MAP kinase activity. In fact, they significantly abrogate the inhibitory effects of estradiol (49), suggesting that inactive estrogens may block the biological effects of estradiol. Indeed, this may explain in part why the use of conjugated estrogens apparently do not reduce cardiovascular risk in postmenopausal women (104). In contrast to estrone and estriol, metabolites of estradiol such as 2-hydroxyestradiol, 2-methoxyestradiol, and 4-methoxyestradiol, which show minimal binding to ER, are more potent inhibitors of mitogen-induced SMC growth compared with estradiol.
Apart from the differential potency of various estrogens on ERs, they also have significant differences in their chemical properties. In this regard, the antioxidant potency of estrone and estriol is much less than estradiol, whereas the catechol estradiols are more potent antioxidants than estradiol. Together, these findings suggest that the biological effects of estrogens may vary considerably.
The above findings may have clinical implications as several different estrogens are used for hormone replacement therapy. Indeed, recent in vitro studies from our laboratory provide evidence that clinically used estrogens differentially inhibit SMC growth and MAP kinase activity (49). Because direct interactions of estrogens with SMCs may be responsible for the protective effects of estrogens on the vasculature, it is feasible that estrogens unable to inhibit SMC growth would be inactive against neointima formation or vasoocclusive disorders.
Another important issue is what concentrations of estradiol are
relevant to physiology. Although most studies use circulating levels of
estradiol (109 mM) as a physiological concentration,
under in vivo conditions estradiol may exist in several biologically
active forms. Thus the levels of estradiol in the plasma may not
reflect the true physiological effects of estradiol. For example, the
concentrations of 2-hydroxyestradiol range between 0.12 and 0.3 µM in
peripheral blood, and the rate of urinary excretion of
2-hydroxyestradiol is 20-180 µg/24 h in urine (6,
78). Finally, the recent finding that vascular SMCs express
aromatase activity and synthesize estradiol (96) suggests
that the local levels of estradiol may be higher.
![]() |
VASCULAR PROTECTIVE EFFECTS OF ESTRADIOL: EPIDEMIOLOGICAL EVIDENCE |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
The evidence for a role of estradiol in regulating vascular structure and function is that ovarian dysfunction and estradiol deficiency are linked to an increased risk of cardiovascular disease in postmenopausal women. Thus compared with men, women within the reproductive age group are protected against cardiovascular disease (143, 203, 296), and these differences decrease with the onset of menopause (143). Also, premenopausal women who undergo premature surgical menopause (i.e., bilateral oophorectomy) have twice the risk of cardiovascular disease than do age-matched premenopausal controls (103, 225).
Because the ovaries are the main source of estradiol production, their dysfunction with age results in a decreased production of estradiol. In this regard, it is important to note that the levels of estradiol, which is the most potent natural estrogen and is largely produced in the ovary, decrease to undetectable levels in postmenopausal women. Compared with estradiol, the levels of other estrogens such as estrone, which can be synthesized in the peripheral compartment, do not fall as dramatically. This suggests that the beneficial effects of ovarian steroids on the cardiovascular system may largely be mediated by estradiol.
Several epidemiological studies demonstrate a reduction in risk of coronary heart disease in postmenopausal women treated with oral estrogen compared with untreated women (25, 83, 203). Three meta-analyses estimate an overall reduction in risk of ~50% for women who had at any time received estrogen therapy. Four studies examine the association between estrogen use and angiographically defined coronary artery disease in postmenopausal women and demonstrate that the calculated odds ratios for severe coronary stenosis or 70% occlusion are 0.50 or lower for estrogen users compared with nonusers. A reduction in mortality among women with diagnosed coronary atherosclerosis is reported in relation to estrogen use (101, 203, 261, 269). Although, estrogen replacement therapy may reduce vasoocclusive disorders in postmenopausal women, hormone replacement therapy using premarin (conjugated estrogen) plus medroxyprogesterone (the HERS study) does not reduce the overall incidence of coronary artery disease in postmenopausal women with established coronary heart disease (104). Several lines of evidence suggest that unlike progesterone, synthetic progestin such as medroxyprogesterone can abrogate the protective effects estradiol on vascular cells. In this regard medroxyprogesterone attenuates the inhibitory effects of estradiol on neointima formation (2, 144) and on NO synthesis (110). Hence it is possible that the lack of effects of estrogen replacement therapy in the HERS study is due to the negative effects of medroxyprogesterone. Alternatively, the lack of effects could also be due to the type of estrogen used. In this regard, our studies show that estrone, estriol, and estrone sulfate, which constitute a major portion of the conjugated estrogen, have little or no inhibitory effects on mitogen-induced SMC growth (53). Because direct interaction of estrogen with SMC in part contributes to the cardioprotective effects of estrogen, it is feasible that the lack of effect of conjugated estrogen is due to the lack of inhibitory estrogen in that specific preparation. Indeed, several studies show that estradiol replacement reduces neointimal thickening in the carotid arteries of postmenopausal women with established coronary artery disease and undergoing percutaneous transdermal coronary angioplasty (203). Taken together, the above findings provide evidence that overall estradiol induces protective antivasoocclusive effects on the cardiovascular system.
Whether estradiol induces antivasoocclusive effects in subjects with established coronary artery disease or has only acute protective effects in patients with minimal occlusive disorders is under intense debate. In this regard, the protective effects of estradiol on the vasculature may depend on the stage or condition of the vascular disease. Indeed, the antiatherogenic effects of estradiol are abolished by balloon catheter injury in cholesterol-clamped rabbits; moreover, the direct antiatherogenic effects of estradiol is present, absent, or reversed depending on the state of the arterial endothelial cells (99). Animal as well as human studies provide convincing evidence that vascular remodeling after balloon injury and percutaneous transdermal coronary angioplasty is significantly inhibited by estradiol. However, estradiol does not prevent neointima formation in a nonhuman primate model with preexisting atherosclerosis (1, 76). Estradiol is able to inhibit the further progression of atherosclerosis in vessel wall with moderate, but not severe, preexisting alterations (89). In contrast, estradiol reduced plaque size and aortic lesion formation in hypocholesterolemic rabbits with severe endothelial dysfunction (189). Future studies should focus on effects of estradiol in vessels with established vasoocclusive disorders.
![]() |
PROTECTIVE EFFECTS OF ESTRADIOL ON THE RENAL SYSTEM: CELLULAR AND BIOCHEMICAL MECHANISMS |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
Women are also protected against the progression of renal disease (255); moreover, gender differences in renal hemodynamics (182) and renal response to ANG II (170) are well established. Results from a meta-analysis performed using 68 studies indicate that men with chronic renal disease of various etiologies show a more rapid decline in renal function with time than do women (192). Ample evidence from epidemiological/clinical studies and from experimental models of renal injury suggest that estradiol is responsible for the resistance of kidneys in women to the progression of renal disease (255, 265).
The potential role of estradiol in regulating renal function is also
evident from the observation that the kidney expresses both the classic
ER- and the newly discovered ER-
. In human fetal kidneys, ER-
is the prominent renal ER expressed, whereas ER-
is only marginally
expressed (24). In contrast, in adult renal tissue, most
studies demonstrate the expression of ER-
, but not ER-
, in
humans, rats, and mice (134, 178, 277). However, ER-
exists in rat kidneys (202). Because ER-
and ER-
respond differently to estradiol in mediating its transcriptional
activity at EREs (120, 178), and respond differentially to
ligands at the AP-1 site (208), it is feasible that the
differential expression of ER subtypes may have important physiological
relevance within the kidney.
Increased generation and deposition of extracellular matrix proteins is
an initial step in the development of glomerular obsolescence and
progressive loss of renal function (47). Estradiol
suppresses collagen synthesis in GMCs (137, 141, 253,
254), suggesting that estradiol may limit the progression of
glomerulosclerosis by reducing matrix accumulation after glomerular
injury. In contrast to SMCs (49), the inhibitory effects
of estradiol on collagen synthesis in GMCs are mediated via activation
of MAP kinase and upregulation of transcription factor AP-1
(253), specifically the c-fos component. However, similar
to the SMCs, the inhibitory effects of estradiol on collagen synthesis
in GMCs is blocked by the ER antagonist ICI-182780, suggesting that the
inhibitory effects are receptor mediated (194); however,
whether ER- or ER-
mediates these effects remains unclear.
In addition to inhibiting serum-induced collagen synthesis, estradiol
also inhibits collagen synthesis induced by ANG II and TGF-
(194, 254), growth factors implicated in the
pathophysiology of progressive renal injury in various experimental
models for kidney disease (21, 250). TGF-
is known to
mediate the mitogenic effects of ANG II as well as ET-1 on SMC and GMC
growth (55, 82). Moreover, estradiol antagonizes the
effects of TGF-
on collagen synthesis in mesangial cells
(254). Because ET-1 and ANG II induce their mitogenic
effects on mesangial cells via TGF-
(116), it is likely
that estradiol also attenuates the deleterious effects of ET-1 and ANG
II on the kidney. Indeed, Neugarten and Silbiger (195)
show that estradiol attenuates the effects of endothelin and ANG II on
mesangial cell collagen synthesis. Thus there is strong evidence that
estradiol protects the kidneys in part by abrogating the mitogenic
effects of multiple growth factors that participate in the
pathophysiology of glomerulosclerosis.
Although estradiol prevents mitogen-induced collagen synthesis, its effects on GMC proliferation are less clear. In cultured GMCs that are not growth arrested, estradiol induces DNA synthesis and proliferation at low concentrations, yet inhibits GMC proliferation at concentrations equal to or greater than 1 µM (137). In contrast, results from our laboratory provide evidence that in growth-arrested GMCs, estradiol inhibits serum-induced DNA synthesis and cell proliferation in a concentration-dependent manner (302a). The disparate effects of estradiol in the two studies may be due to the culture conditions. In this regard, estradiol induces MAP kinase activity in mesangial cells that are not growth arrested, whereas in growth-arrested (serum-starved) GMCs estradiol has no effect on basal MAP kinase activity and inhibits PDGF-induced and ANG II-induced MAP kinase activity (194). Because PDGF-BB and ANG II are known to induce cell proliferation via activation of MAP kinase activity (5355, 176) and estradiol inhibits these effects, it is feasible that estradiol may abrogate the promitogenic effects of ANG II and PDGF on GMCs. Because increased proliferation of GMCs plays a key role in glomerulosclerosis, estradiol may protect against glomerular remodeling by inhibiting cell growth. However, future studies are required to investigate this possibility in more detail.
Estradiol may also influence GMC growth indirectly by influencing the synthesis of growth promoters and growth inhibitors. In this regard, estradiol downregulates the synthesis of several molecules that are known to induce GMC growth and glomerulosclerosis. Estradiol lowers circulating and renal levels of ANG II by downregulation of ACE activity (71), suggesting that estradiol may protect the kidney by inhibiting the synthesis of ANG II. Estradiol lowers the production of ET-1 (177, 304), ET-1 is a mitogen for GMCs (55), and increased production of ET-1 by glomerular cells is associated with glomerulosclerosis (55). It is feasible, therefore, that the inhibitory effects of estradiol on ET-1 synthesis would protect the kidney against glomerular remodeling. Estradiol also decreases the levels of homocysteine (79, 283), and homocysteine is known to cause glomerular damage and induce glomerulosclerosis (159).
Several lines of evidence suggest that ANG II stimulates ET-1 synthesis, and ET-1 increases the conversion of ANG I to ANG II, an effect that can be blocked by ACE inhibitors (55). These findings suggest that increased generation of ET-1 within glomeruli may lead to increases in ANG II, synthesis which in turn would upregulate ET-1 synthesis (57, 82). Generation of ANG II and ET-1 through this vicious cycle might importantly modulate renovascular tone and growth of GMCs, thus leading to renal dysfunction (55). The fact that estradiol downregulates ACE activity and ET-1 synthesis suggests that estradiol may protect against glomerular remodeling by blocking this vicious cycle of ANG II and ET-1 synthesis. In the same vein, estradiol also downregulates the synthesis of both IGF-1 and IGF-I receptor (155, 156). Because IGF-1 is a potent mitogen for GMCs (55), it is feasible that estradiol may abrogate the promitogenic effects of IGF-1 on GMCs and protect against glomerular remodeling.
Another important molecule that regulates GMC growth and participates
in glomerular remodeling is plasminogen activator inhibitor-1 (PAI-1;
14, 55). It is a key regulator of the plasmin-mediated proteolytic
cascade that modulates fibrinolysis, ECM turnover, and degradation and
regulation of cell migration (55). PAI-1, via inhibition
of proteolytic cascades (plasminogen activator and urokinase
plasminogen activator), induces abnormal growth and ECM synthesis in
the glomerulus (14, 55). The finding that estradiol lowers
PAI-1 levels by ~50% (128) suggests that estradiol may
protect against the promitogenic and deleterious effects of PAI-1 on
GMCs. PAI-1 activity is regulated by ANG II (55), and
inhibition of ACE results in reduced expression of PAI-1 and ECM
deposition in glomerulosclerosis (55). Indeed, PAI-1
synthesis is increased in glomerular cells of sclerotic kidneys
(14, 55). Moreover, TGF-, which mediates the mitogenic effects of ANG II on GMCs, is known to induce PAI-1 expression in GMCs
(303). The above findings, along with the fact that
estradiol inhibits ANG II synthesis and downregulates TGF-
expression, suggest that inhibitory effects of estradiol on these
molecules would result in decreased PAI-1 synthesis, and this in turn
would protect the GMCs against cell proliferation, collagen synthesis, and glomerular remodeling.
In addition to the above factors, growth within the glomerulus is also stimulated by free radicals (55). Free radicals induce GMC cell growth (55) and contribute to the process of glomerulosclerosis in various renal diseases (86). The mechanism by which free oxygen radicals induce their mitogenic effects on GMCs include induction of ET-1 synthesis, oxidation of LDL to oxidized LDL, oxidation of lipoproteins, and activation of the MAP kinase pathway (55). Because estradiol is a potent antioxidant that scavenges free radicals, estradiol may protect GMCs against the growth effects of free radicals. Indeed, oxidation of LDL to oxidized LDL by mesangial cells is blocked by estradiol (194), and estradiol blocks the effects of free radicals on cell growth and lipid peroxidation in SMCs (30, 56), which are phenotypically similar to GMCs. In hypercholesterolemic female rats, ovariectomy induces glomerular injury, and this effect is reversed by 0.2 mg, but not 0.1 mg, of estradiol (240). These studies provide evidence that antioxidant effects of estradiol may protect against glomerular remodeling. However, further studies are required to conclusively demonstrate whether estradiol blocks free radical-induced mitogenesis in GMCs.
The growth inhibitory and protective effects of estradiol on the kidney are also supported by recent in vivo studies. Mulroney et al.(181) report that after unilateral nephrectomy, male remnant kidneys grow by 117% whereas female remnant kidneys grow by only 57%. Also, compared with control kidneys, glomerular volume of male remnant kidneys increases by 126% whereas in females no changes in glomerular volume are observed. In contrast to that in males, no glomerular or tubular damage is observed in female remnant kidneys. Studies in ovarectomized female rats show that the deleterious effects in males are due to testosterone, whereas estradiol is protective (180, 181) .
Abnormal growth within the glomerulus is also a key factor in chronic
renal allograft rejection, and estradiol protects the vasculature
against allograft-induced dysplasia. Indeed, compared with
testosterone, estradiol treatment improves graft function, reduces
glomerulosclerosis, and diminishes cellular infiltration (180). Moreover, these changes are accompanied by reduced
ICAM-1, fibronectin, laminin, and TGF-. These findings suggest that
estradiol induces protective effects on the kidney and protects against glomerulosclerosis.
One of the major factors involved in regulating renal function is NO. Gender differences in renal NO synthesis are reported by Reckelhoff et al. (220), who demonstrate that the levels of eNOS are 80% higher in women than in men. Although basal synthesis of NO is protective, excessive synthesis of NO may induce deleterious effects on the kidney. Indeed, increased NO synthesis by activated monocytes/macrophages infiltrating the glomeruli causes glomerular injury (119, 188). Increased NO synthesis in acute glomerulonephritis in rats causes lysis of GMCs and accumulation of ECM (188). Moreover, inhibition of NO synthesis by NG-monomethyl-L-arginine reverses some of these effects, suggesting that inhibition of NOS may protect against the deleterious effects of NO (305). Estradiol upregulates eNOS (NOS I) essential for normal renal function; however, it inhibits iNOS (NOS II), suggesting that estradiol may prevent the deleterious effects of NO by downregulating iNOS-derived NO. Importantly, estradiol inhibits iNOS activity in activated macrophages/monocytes, which play a critical role in inflammatory glomerulonephritis, in experimental models of anti-thy 1 glomerulonephritis and in lupus glomerulonephritis (93, 271). Together, these findings suggest that estradiol may protect the kidney by abrogating the deleterious effects of iNOS-derived NO. In contrast to the above studies, Neugarten et al. (193) report stimulatory effects of estradiol on renal iNOS. Hence the interactive role of NO and estradiol in glomerulosclerosis needs to be further investigated.
Although mesangial cells importantly contribute to the glomerular
remodeling process, injury to glomerular endothelial cells (GECs) also
participates in this process (111, 140). Growth of GECs
participate in capillary repair of glomerulonephritis (206). Because estradiol induces growth of aortic ECs
(124, 258), it is feasible that estradiol may also
facilitate the glomerular repair process by inducing growth of GECs. In
this regard, it is interesting to note that in vascular ECs estradiol
induces VEGF synthesis (272), and VEGF is known to repair
GEC injury (206), suggesting that estradiol may
protect the glomeruli by inducing VEGF synthesis in GEC. However, this
possibility remains to be investigated. In the same vein, estradiol
prevents TNF- and LPS-induced apoptosis of vascular ECs
(258). Because TNF-
and LPS induce apoptotic death
of GECs (167), it is feasible that estradiol may also
prevent the deleterious effects of TNF-
and LPS on GECs.
Other mechanisms that may contribute to the renoprotective effects of estrogen include inhibition of mesangial cell apoptosis (257); upregulation of antiaggregatory pathways by induction of ecto-ADPase in glomeruli and the vessel wall (60); upregulation of renal oxytocin receptor gene expression responsible for regulating renal fluid dynamics (207); prevention of urinary stone formation with inhibition of crystal deposition and calcium content in renal tissue; decrease in urinary excretion of oxalate and downregulation of the expression of osteopontin mRNA in renal tissue (109); upregulation of the synthesis of antimitogenic prostaglandins (33, 115, 169); attenuation of IgA-induced nephropathy (85); and upregulation of adenosine synthesis in SMCs, which is renoprotective (52). Finally, recent studies from our laboratory provide evidence that 2-hydroxyestradiol and 2-methoxyestradiol are more potent than estradiol in inhibiting serum-induced growth of GMCs (302a), suggesting that the antimitogenic and glomeruloprotective effects of estradiol can also be mediated via its metabolites. Because these metabolites have low or negligible affinity for ER, the effects are mediated via an ER-independent mechanism.
Defective metabolism of estradiol induces deleterious effects on the kidneys. For instance, in Syrian hamsters estradiol induces tumor formation and causes cancer, and these effects are thought to be mediated via the estradiol metabolite 4-hydroxyestradiol (148). Indeed, compared with the 2-hydroxylation pathway, the 4-hydroxylation pathway is more prominent in the kidneys of hamsters (307). Because 4- hydroxyestradiol, but not 2-hydroxyestradiol, is carcinogenic (307), the explanation for the specific carcinogenic effects of estradiol in hamster kidneys may lie in the fact that the reproductive and the urogenital tracts of the Syrian hamsters arise from the same embryonic germinal ridge (125). Because estradiol is known to induce cancer within the reproductive tissue, it is feasible that hamster kidneys may carry the cancer genes that are expressed and responsive to estradiol (102). In hamster kidneys, estradiol upregulates c-myc and c-jun genes that stimulate cell proliferation (19, 146), induces cathepsin D protein (147), and induces lipid peroxidation and DNA adduct formation (291). However, these deleterious effects are specific for the Syrian hamsters as the CYP450 enzymes responsible for the metabolism of estradiol to 4-hydroxyestradiol (a carcinogen) are more prominent, and the enzymes responsible for counteracting these effects via generation of 2-hydroxyestradiol or detoxification via methylation are downregulated (307).
In constrast to the aforementioned renoprotective effects, estradiol enhances gentamicin-induced nephrotoxicity (29); induces glomerulosclerosis in analbuminemic rats (114) and fibrosis in corticomedullary junction in Beagle dogs (314); significantly increases the rate of nephropathy in Cohen diabetic rats (226) and rate of glomerulonephrites associated with experimental lupus nephrites (28); and aggravates the progression of renal diseases that are characterized by the nephrotic syndrome via increased levels of serum triglycerides with resultant triglyceride-mediated renal injury (114, 264).
![]() |
CONCLUSION |
---|
There is overwhelming evidence that, in addition to being a
reproductive hormone, estradiol induces protective effects on the
cardiovascular and renal systems (Table
1). However, these protective effects are
modulated by various factors (Table 1). In this regard, drug-drug
interactions, binding affinity to specific ER subtypes types,
expression of specific ER subtypes, and metabolism of estradiol locally
within the tissue as well as by the liver all influence the effects of
estrogen on the vasculature, heart, and kidneys.
|
![]() |
ACKNOWLEDGEMENTS |
---|
This work was supported by grants from the Swiss National Science Foundation (32-54172.98), the National Heart, Lung, and Blood Institute (HL-55314 and HL-35909), and by an unconditional educational grant from Schering (Schweiz) AG.
![]() |
FOOTNOTES |
---|
Address for reprint requests and other correspondence: R. K. Dubey, Clinic for Endocrinology, Dept. of Obstetrics and Gynecology, Univ. Hospital Zurich, Frauenklinikstrasse 10, CH-8051 Zurich, Switzerland (E-mail: Raghvendra.Dubey{at}fhk.usz.ch).
![]() |
REFERENCES |
---|
1.
Adams, MR,
Kaplan JR,
Manuck SB,
Koritnik DR,
Parks JS,
Wolfe MS,
and
Clarkson TB.
Inhibition of coronary artery atherosclerosis: lack of effect of added progesterone.
Arteriosclerosis
10:
1051-1057,
1990[Abstract].
2.
Adams, MR,
Register TC,
Golden DL,
Wagner JD,
and
Williams JK.
Medroxyprogesterone acetate antagonizes inhibitory effects of conjugated equine estrogens on coronary artery atherosclerosis.
Arteriosclerosis Thromb Vasc Biol
17:
217-221,
1997
3.
Akishita, M,
Kozaki K,
Eto M,
Yoshizumi M,
Ishikawa M,
Toba K,
Orimo H,
and
Ousch Y.
Estrogen attenuates endothelin-1 production by bovine endothelial cells via estrogen receptor.
Biochem Biophys Res Commun
251:
17-21,
1998[ISI][Medline].
4.
Akishita, M,
Ouchi Y,
Miyoshi H,
Kozaki K,
Inoue S,
Ishikawa M,
Eto M,
Toba K,
and
Orimo H.
Estrogen inhibits cuff-induced intimal thickening of rat femoral artery: effects on migration and proliferation of vascular smooth muscle cells.
Atherosclerosis
130:
1-10,
1997[ISI][Medline].
5.
Albuquerque, ML,
Akiyama SK,
and
Schnaper HW.
Basic fibroblast growth factor release by human coronary artery endothelial cells is enhanced by matrix proteins, 17beta-estradiol, and a PKC signaling pathway.
Exp Cell Res
245:
163-169,
1998[ISI][Medline].
6.
Aldercreutz, H,
Gorbach SL,
Goldin BR,
Woods MN,
Dwyer JT,
and
Hamalainen E.
Estrogen metabolism and excretion in Oriental and Caucasian women.
J Natl Cancer Inst
86:
1076-1082,
1994[Abstract].
7.
Ali, SH,
O'Donnell AL,
Mohamed S,
Mousa S,
and
Dandona P.
Stable over-expression of estrogen receptor-alpha in ECV304 cells inhibits proliferation and levels of secreted endothelin-1 and vascular endothelial growth factor.
Mol Cell Endocrinol
152:
1-9,
1999[ISI][Medline].
8.
Alvarez, RJ,
Gips SJ,
Moldovan N,
Wilhide CC,
Milliken EE,
Hoang AT,
Hruban RH,
Silverman HS,
Dang CV,
and
Goldschmidt-Clermont PJ.
17-Estradiol inhibits apoptosis of endothelial cells.
Biochem Biophys Res Commun
237:
372-381,
1997[ISI][Medline].
9.
Aronica, SM,
Kraus WL,
and
Katzenellenbogen BS.
Estrogen action via the cAMP signaling pathway: stimulation of adenylate cyclase and cAMP-regulated gene transcription.
Proc Natl Acad Sci USA
91:
8517-8521,
1994[Abstract].
10.
Asahara, T,
Bauters C,
Zheng LP,
Takeshita S,
Bunting S,
Ferrara N,
Symes JF,
and
Inser JM.
Synergistic effect of vascular endothelial growth factor and basic fibroblast growth factor on angiogenesis in vivo.
Circulation
92, Suppl 9:
365-371,
1995
11.
Bakir, S,
Mori T,
Durand J,
Chen YF,
Thompson JA,
and
Oparil S.
Estrogen-induced vasoprotection is estrogen receptor dependent. Evidence from the balloon-injury rat carotid artery model.
Circulation
101:
2342-2345,
2000
12.
Ball, P,
and
Knuppen R.
Formation, metabolism, and physiologic importance of catecholestrogens.
Am J Obstet Gynecol
163:
2163-2170,
1990[ISI][Medline].
13.
Barbacanne, MA,
Rami J,
Michel JB,
Souchard JP,
Philippe M,
Besombes JP,
Bayard F,
and
Arnal JF.
Estradiol increases rat aorta endothelium-derived relaxing factor (EDRF) activity without changes in endothelial NO synthase gene expression: possible role of decreased endothelium-derived superoxide anion production.
Cardiovasc Res
41:
672-681,
1999[ISI][Medline].
14.
Barcios, WH,
Cortez SL,
El-Dahr SS,
and
Schnaper HW.
ECM degradation by cultured human mesangial cells is mediated by a PA/plasmin/MMP-2 cascade.
Kidney Int
47:
1039-1047,
1995[ISI][Medline].
15.
Bayard, F,
Clamens S,
Meggetto F,
Blaes N,
Delsol G,
and
Faye JC.
Estrogen synthesis, estrogen metabolism, and functional estrogen receptors in rat arterial smooth muscle cells in culture.
Endocrinology
136:
1523-1529,
1995[Abstract].
16.
Behl, C,
Widmann M,
Trapp T,
and
Holsboer F.
17-Estradiol protects neurons from oxidative stress-induced cell death in vitro.
Biochem Biophys Res Commun
216:
473-482,
1995[ISI][Medline].
17.
Beldekas, JC,
Smith B,
Gerstenfeld LC,
Sonenshein GE,
and
Franzblau C.
Effects of 17-estradiol on the biosynthesis of collagen in cultured bovine aortic smooth muscle cells.
Biochemistry
20:
2162-2167,
1981[ISI][Medline].
18.
Berlotti, M,
and
Spady DK.
Effect of hypocholesterolemic doses of 17-ethinyl estradiol on cholesterol balance in liver and extrahepatic tissues.
J Lipid Res
37:
1812-1822,
1996[Abstract].
19.
Bhat, HK,
Springer I,
Rajaraman S,
and
Liehr JG.
Immunocytochemical localization of c-myc and c-jun oncoproteins in hamster kidney and estrogen-induced kidney tumors.
J Steroid Mol Biol
60:
99-104,
1997[ISI].
20.
Binko, J,
and
Majewski H.
17-Estradiol reduces vasoconstriction in endothelium-denuded rat aortas through inducible NOS.
Am J Physiol Heart Circ Physiol
274:
H853-H859,
1998
21.
Border, WA,
and
Noble NA.
Transforming growth factor in tissue fibrosis.
N Engl J Med
331:
1286-1291,
1994
22.
Bornfeld, KE,
Raines EW,
Nakano T,
Graves LM,
Krebs EG,
and
Ross R.
Insulin like growth factor-1 and platelet derived growth factor BB induce directed migration of human srterial smooth muscle cells via signalling pathways that are distinct from those of proliferation.
J Clin Invest
93:
1266-1274,
1994[ISI][Medline].
23.
Bourassa, PAK,
Milos PM,
Caynor BJ,
Breslow JL,
and
Aiello RJ.
Estrogen reduces atherosclerotic lesion development in apolipoprotein E-deficient mice.
Proc Natl Acad Sci USA
93:
10022-10027,
1996
24.
Brandenberger, AW,
Tee MK,
Lee JY,
Chao V,
and
Jaffe RB.
Tissue distribution of estrogen receptors alpha (ER-alpha) and beta (ER-beta) mRNA in the midgestational human fetus.
J Clin Endocrinol Metab
82:
3509-3512,
1997
25.
Bush, TL.
Evidence for primary and secondary prevention of coronary artery disease in women taking oestrogen replacement therapy.
Eur Heart J
17, SupplD:
9-14,
1996[ISI][Medline].
26.
Cambotti, LJ,
Cole FE,
Gerall AA,
Frohlich ED,
and
MacPhee AA.
Neonatal gonadal hormones and blood pressure in the spontaneously hypertensive rat.
Am J Physiol Endocrinol Metab
247:
E258-E264,
1984
27.
Campos, H,
Walsh BW,
Judge H,
and
Sacks FM.
Effect of estrogen on very low density lipoprotein and low density lipoprotein subclass metabolism in postmenopausal women.
J Clin Endocrinol Metab
82:
3955-3963,
1997
28.
Carlstein, H,
Nilsson N,
Jonsson R,
and
Tarkowski A.
Differential effects of estrogen in murine lupus: accleration of glomerulonephritis and amelioration of T cell-mediated lesions.
J Autoimmun
4:
845-856,
1991[ISI][Medline].
29.
Carraro-Eduardo, JC,
Oliveira AV,
Carrapatoso ME,
and
Ornellas JF.
Effect of sex hormones on gentamicin-induced nephrotoxicity.
Braz J Med Biol Res
26:
653-662,
1993[ISI][Medline].
30.
Cathapermal, S,
Lavinge MC,
Leong-Son M,
Alibadi T,
and
Ramwell PW.
Stereoisomer-specific inhibition of superoxide anion-induced rat aortic smooth-muscle cell proliferation by 17-estradiol is estrogen receptor dependent.
J Cardiovasc Pharmacol
31:
499-505,
1998[ISI][Medline].
31.
Caulin-Glaser, T,
Garcia-Cardena G,
Sarrel P,
Sessa WC,
and
Bender JR.
17-Estradiol regulation of human endothelial cell basal nitric oxide release, independent of cytosolic Ca2+ mobilization.
Circ Res
81:
885-892,
1997
32.
Caulin-Glaser, T,
Watson CA,
Pardi R,
and
Bender JR.
Effects of 17-estradiol on cytokine-induced endothelial cell adhesion molecule expression.
J Clin Invest
98:
36-42,
1996
33.
Chang, WC,
Nakao J,
Orimo H,
and
Murota SI.
Stimulation of prostaglandin cyclooxygenase and prostacyclin synthase activities by estradiol in rat aortic smooth muscle cells.
Biochem Biophys Acta
620:
472-482,
1980[ISI][Medline].
34.
Chen, SJ,
Li H,
Durand J,
Oparil S,
and
Chen YF.
Estrogen reduces myointimal proliferation after balloon injury of rat carotid artery.
Circulation
93:
577-584,
1996
35.
Chen, Z,
Yuhanna IS,
Galcheva-Gargova Z,
Karas RH,
Mendelsohn ME,
and
Shaul PW.
Estrogen receptor mediates the nongenomic activation of endothelial nitric oxide synthase by estrogen.
J Clin Invest
103:
401-406,
1999
36.
Cheng, LP,
Kuwahara M,
Jacobsson J,
and
Foegh ML.
Inhibition of myointimal hyperplasia and macrophage infiltration by estradiol in aorta allografts.
Transplantation
52:
967-972,
1991[ISI][Medline].
37.
Christ, M,
Gunther A,
Heck M,
Schmidt BM,
Falkenstein E,
and
Wehling M.
Aldosterone, not estradiol, is the physiological agonist for rapid increases in cAMP in vascular smooth muscle cells.
Circulation
99:
1485-1491,
1999
38.
Collins, P,
Rosano GMC,
Sarrel PM,
Ulrich L,
Adamopoulos S,
Beale CM,
McNeill JG,
and
Poole-Wilson PA.
17-Estradiol attenuates acetylcholine-induced coronary arterial constriction in women but not men with coronary heart disease.
Circulation
92:
24-30,
1995
39.
Collins, P,
Shay J,
Jiang C,
and
Moss J.
Nitric oxide accounts for dose-dependent estrogen-mediated coronary relaxation after acute estrogen withdrawl.
Circulation
90:
1964-1968,
1994[Abstract].
40.
Collins, T,
Read MA,
Neish AS,
Whitley MZ,
Thanos D,
and
Maniatis T.
Transcriptional regulation of endothelial cell adhesion molecules: NF- and cytokine inducible enhancers.
FASEB J
9:
899-909,
1995
41.
Colvin, PL, Jr.
Estrogen increases low-density receptor-independent catabolism of apolipoprotein B in hyperlipidemic rabbits.
Metabolism
45:
889-896,
1996[ISI][Medline].
42.
Cominacini, L,
Garbin U,
Pasini AF,
Davoli A,
Campagnola M,
Contessi GB,
Pastorino AM,
and
LoCascio V.
Antioxidants inhibit the expression of intercellular cell adhesion molecule-1 and vascular cell adhesion molecule-1 induced by oxidized LDL on human umbilical vein endothelial cells.
Free Radic Biol Med
22:
117-127,
1997[ISI][Medline].
43.
Crofton, JT,
and
Share L.
Gonadal hormones modulate deoxycorticosterone-salt hypertension in male and female rats.
Hypertension
29:
494-499,
1997
44.
Darkow, DJ,
Lu L,
and
White RE.
Estrogen relaxation of coronary artery smooth muscle is mediated by nitric oxide and cGMP.
Am J Physiol Heart Circ Physiol
272:
H2765-H2773,
1997
45.
Delarue, F,
Daunes S,
Elhage R,
Garcia A,
Bayard F,
and
Faye J.
Estrogens modulate bovine vascular endothelial cell permeability and HSP25 expression concomitantly.
Am J Physiol Heart Circ Physiol
275:
H1011-H1015,
1998
46.
Demacker, PN,
Staels B,
Stalenhoef AF,
and
Auwerx J.
Increased removal of beta-very low density lipoproteins after ethinyl estradiol is associated with increased mRNA levels for hepatic lipase, lipoprotein lipase and low density lipoprotein receptor in Watanabe hyperlipidemic rabbits.
Arterioscler Thromb Vasc Biol
11:
1652-1659,
1991[Abstract].
47.
Diamond, JR,
and
Karnovsky MJ.
Focal and segmental glomerulosclerosis: analogies to atherosclerosis.
Kidney Int
33:
917-924,
1988[ISI][Medline].
48.
Di Croce, L,
Bruscalupi G,
and
Trentalance A.
Independent behavior of rat liver LDL receptor and HMGCoA reductase under estrogen treatment.
Biochem Biophys Res Commun
16:
345-350,
1996.
49.
Dubey, RK.
Vasodilator-derived nitric oxide inhibits fetal calf serum and angiotensin II-induced growth of renal arteriolar smooth muscle cells.
J Pharmacol Exp Ther
269:
402-408,
1994[Abstract].
50.
Dubey, RK,
Gillespie DG,
Imthurn B,
Rosselli M,
Jackson EK,
and
Keller PJ.
Phytoestrogens inhibit growth and MAP kinase activity in human aortic smooth muscle cells.
Hypertension
33:
177-182,
1999
51.
Dubey, RK,
Gillespie DG,
Jackson EK,
and
Keller PJ.
17-Estradiol, its metabolites and progesterone inhibit cardiac fibroblast growth.
Hypertension
31:
522-528,
1998
52.
Dubey, RK,
Gillespie DG,
Mi Z,
Rosselli M,
Keller PJ,
and
Jackson EK.
Estradiol inhibits smooth muscle cell growth in part by activating the cAMP-adenosine pathway.
Hypertension
35:
262-266,
2000
53.
Dubey, RK,
Gillespie DG,
Zacharia LC,
Imthurn B,
Jackson EK,
and
Keller PJ.
Clinically used estrogens differentially inhibit human aortic smooth muscle cell growth and MAP kinase activity.
Arterioscler Thromb Vasc Biol
20:
964-972,
2000
53a.
Dubey, RK,
Gillespie DG,
Zacharia LC,
Rosselli M,
Korzekwa KR,
Fingerle J,
and
Jackson EK.
Methoxyestradiols mediate the antimitogenic effects of estradiol on vascular smooth muscle cells via estrogen receptor-independent mechanisms.
Biochem Biophys Res Commun
278:
27-33,
2000[ISI][Medline].
54.
Dubey, RK,
Jackson EK,
and
Luscher TF.
Nitric oxide inhibits angiotensin II-induced migration of rat aortic smooth muscle cell. Role of cyclic-nucleotides and angiotensin 1 receptors.
J Clin Invest
96:
141-149,
1995[ISI][Medline].
55.
Dubey, RK,
Jackson EK,
Rupperecht H,
and
Sterzel RB.
Factors controlling growth and matrix production in vascular smooth muscle and glomerular mesangial cells.
Curr Opin Nephrol Hypertens
6:
88-105,
1997[ISI][Medline].
56.
Dubey, RK,
Tyurina YY,
Tyurin VA,
Gillespie DG,
Branch RA,
Jackson EK,
and
Kagan VE.
Estrogen and tamoxifen metabolites protect smooth muscle cell membrane phospholipids against peroxidation and inhibit cell growth.
Circ Res
84:
229-239,
1999
57.
Egido, J.
Vasoactive hormones and renal sclerosis.
Kidney Int
49:
578-597,
1996[ISI][Medline].
58.
Elhage, R,
Bayard F,
Richard V,
Holvoet P,
Duverger N,
Fievet C,
and
Arnal JF.
Prevention of fatty streak formation of 17-estradiol is not mediated by the production of nitric oxide in apolipoprotein E-deficient mice.
Circulation
96:
3048-3052,
1997
59.
Enmark, E,
Pelto-Huikko M,
Grandien K,
Lagercrantz S,
Lagercrantz J,
Nordenskjold M,
and
Gustafsson JA.
Human estrogen receptor beta-gene structure, chromosomal localisation and expression pattern.
J Clin Endocrinol Metab
82:
4258-4265,
1997
60.
Faas, MM,
Bakker WW,
Klok PA,
Baller JF,
and
Schuiling GA.
Modulation of glomerular ECTO-ADPase expression by oestradiol. A histochemical study.
Thromb Haemost
77:
767-771,
1997[ISI][Medline].
61.
Farhat, MY,
Abi-Younes S,
Dingaan B,
Vargas R,
and
Ramwell PW.
Estradiol increases cyclic adenosine monophosphate in rat pulmonary vascular smooth muscle cells by a nongenomic mechanism.
J Pharmacol Exp Ther
276:
652-657,
1996[Abstract].
62.
Farhat, MY,
Lavigne MC,
and
Ramwell PW.
The vascular protective effects of estrogen.
FASEB J
10:
615-624,
1996
63.
Fernandez-Alfonso, MS,
Martorana PA,
Licka I,
van Even P,
Trobisch D,
and
Scholkens BA.
Early induction of angiotensin I-converting enzyme in rat carotid artery after balloon injury.
Hypertension
30:
272-277,
1997
64.
Fischer, GM,
Cherian K,
and
Swain ML.
Increased synthesis of aortic collagen and elastin in experimental atherosclerosis: inhibition by contraceptive steroids.
Atherosclerosis
39:
463-467,
1981[ISI][Medline].
65.
Foegh, ML,
Asotra S,
Howell MH,
and
Ramwell PW.
Estradiol inhibition of arterial neointimal hyperplasia after balloon injuy.
J Vasc Surg
19:
722-726,
1994[ISI][Medline].
66.
Foegh, ML,
Khirabadi BS,
Nakanishi T,
Vargas R,
and
Ramwell PW.
Estradiol protects against experimental cardiac transplant atherosclerosis.
Transplant Proc
19, Suppl5:
90-95,
1987[ISI][Medline].
67.
Foegh, ML,
and
Ramwell PW.
Cardiovascular effects of estrogen: implications of the discovery of the estrogen receptor subtype .
Curr Opin Nephrol Hypertens
7:
83-89,
1998[ISI][Medline].
68.
Foegh, ML,
Zhao Y,
Farhat M,
and
Ramwell PW.
Oestradiol inhibition of vascular myointimal proliferation following immune, chemical and mechanical injury.
Ciba Found Symp
191:
139-145,
1995[ISI][Medline].
69.
Fostis, T,
Zhang Y,
Pepper MS,
Adlercreutz H,
Montesano R,
Nawroth PP,
and
Schweigere L.
The endogenous oestrogen metabolite 2-methoxyestradiol inhibits angiogenesi and suppresses tumor growth.
Nature
17:
237-239,
1994.
70.
Frost, PH,
Davis BR,
Burlando AJ,
Curb JD,
Guthrie GP, Jr,
Isaacsohn JL,
Wassertheil-Smoller S,
Wilson AC,
and
Stamler J.
Serum lipids and incidence of coronary heart disease. Findings from the systolic hypertension in the elderly program (SHEP).
Circulation
94:
2381-2388,
1996
71.
Gallagher, PE,
Li P,
Lenhart JR,
Chappell MC,
and
Broshihan KB.
Estrogen regulation of angiotensin-converting enzyme mRNA.
Hypertension
33:
323-328,
1999
72.
Garcia-Rodriguez, LA,
and
Jick H.
Risk of gyneacomastia associtated with cimetidin, omeprazole, and other antinuclear drug.
Br Med J
308:
503-536,
1994
73.
Gardner, G,
Banka CL,
Roberts KA,
Mullick AE,
and
Rutledge JC.
Modified LDL-mediated increases in endothelial layer permeability are attenuated with 17 beta-estradiol.
Arterioscler Thromb Vasc Biol
19:
854-861,
1999
74.
Garg, UC,
and
Hassid S.
Nitric oxide generating vasodilators and 8-bromo-cyclic guanosine monophosphate inhibit mitogenesis and proliferation of cultured rat vascular smooth muscle cells.
J Clin Invest
97:
2377-2383,
1989
75.
Gaub, MP,
Bellard M,
Scheuer I,
Chambon P,
and
Sassone-Corsi P.
Activation of ovalbumin gene by the estrogen receptor involves the fos-jun complex.
Cell
63:
1267-1276,
1990[ISI][Medline].
76.
Geary, RL,
Adams MR,
Benjamin ME,
and
Williams JK.
Conjugated equine estrogens inhibit progression of atherosclerosis but have no effect on intimal hyperplasia or arterial remodeling induced by balloon catheter injury in monkeys.
J Am Coll Cardiol
31:
1158-1164,
1998[ISI][Medline].
77.
Gebara, OCE,
Mittleman MA,
Sutherland P,
Lipinska I,
Matheney T,
Xu P,
Welty FK,
Wilson PWF,
Levy D,
Muller JE,
and
Tofler GH.
Association between increased estrogen status and increased fibrinolytic potential in the Framingham Offspring Study.
Circulation
91:
1952-1958,
1995
78.
Gilabert, J,
Estelles A,
Cano A,
Espana F,
Barrachina R,
Grancha S,
Aznar J,
and
Tortajada M.
Am J Obstet Gynecol
173:
1849-1854,
1995[ISI][Medline].
79.
Gilaty, EJ,
Hoogeveen EK,
Elbers JM,
Gooren LJ,
Asschemen H,
and
Stehouwer CD.
Effects of sex steroids on plasma total homocysteine levels: a study in transsexual males and females.
J Clin Endocrinol Metab
83:
550-553,
1998
80.
Gilligan, DM,
Badar DM,
Panza JA,
Quyyumi AA,
and
Cannon RO, III.
Acute vascular effects of estrogen in postmenopausal women.
Circulation
90:
786-791,
1994[Abstract].
81.
Goetz, RM,
Thatte HS,
Prabhakar P,
Cho MR,
Michel T,
and
Golan DE.
Estradiol induces the calcium-dependent translocation of endothelial nitric oxide synthase.
Proc Natl Acad Sci USA
96:
2788-2793,
1999
82.
Gomez-Garre, D,
Ruiz-Ortega M,
Ortego M,
Largo R,
Lopez-Armada MJ,
Plaza JJ,
Gonzalez E,
and
Egido J.
Effects and interactions of endothelin-1 and angiotenin-II on matrix protein expression and synthesis and mesangial cell growth.
Hypertension
27:
885-892,
1996
83.
Grady, D,
Rubin SM,
Petitti DB,
Fox CS,
Black D,
Ettinger B,
Ernster VL,
and
Cummings SR.
Hormone therapy to prevent disease and prolong life in postmenopausal women.
Ann Intern Med
117:
1016-1037,
1992[ISI][Medline].
84.
Green, S,
Walter P,
Kumar V,
Krust A,
Bornert JM,
Argos P,
and
Chambon P.
Human estrogen receptor cDNA: sequence, expression and homology to v-erb-A.
Nature
320:
134-139,
1986[ISI][Medline].
85.
Greene, DM,
Azcona-Olivera JI,
Murtha JM,
and
Pestka JJ.
Effects of dihydrotestosterone and estradiol on experimental IgA nephroparhy induced by vomitoxin.
Fundam Appl Toxicol
26:
107-116,
1995[ISI][Medline].
86.
Grone, HJ,
Hohbach J,
and
Grone EF.
Modulation of glomerular sclerosis and interstitial fibrosis by native and modified lipoproteins.
Kidney Int
49, Suppl 54:
S18-S22,
1996[ISI].
87.
Guetta, V,
Quyyumi AA,
Prasad A,
Panza JA,
Waclaeiw M,
and
Cannon RO.
The role of nitric oxide in coronary vascular effects of estrogen in postmenopausal women.
Circulation
96:
2795-2801,
1997
88.
Hanke, H,
Hanke S,
Bruck B,
Brehme U,
Gugel N,
Fincking G,
Muck AO,
Schmahl FW,
Hombach V,
and
Haasis R.
Inhibition of the protective effects of estrogen by progesterone in experimental atherosclerosis.
Atherosclerosis
121:
129-138,
1996[ISI][Medline].
89.
Hanke, H,
Kamenz J,
Hanke S,
Spiess J,
Lenz C,
Brehme U,
Bruck B,
Finking G,
and
Hombach V.
Effect of 17- estradiol on pre-existing atherosclerotic lesions: role of the endothelium.
Atherosclerosis
147:
123-132,
1999[ISI][Medline].
90.
Harada, N,
Sasano H,
Murakami H,
Ohkuma T,
Nagura H,
and
Takagi Y.
Localized expression of aromatase in human vascular tissues.
Circ Res
84:
1285-1291,
1999
91.
Harrison, RL,
and
McKee PA.
Estrogen stimulates van Willebrand factor production by cultured endothelial cells.
Blood
63:
657-664,
1984[Abstract].
92.
Hassager, C,
Riis BJ,
Strom V,
Guyene TT,
and
Christiansen C.
The long-term effect of oral and percutaneous estradiol on plasma renin substrate and blood pressure.
Circulation
76:
753-758,
1987[Abstract].
93.
Hayashi, T,
Yamada K,
Esaki T,
Muto E,
Chaudhari G,
and
Iguchi A.
Physiological concentrations of 17-estradiol inhibit the synthesis of nitric oxide synthase in macrophages via a receptor-mediated system.
J Cardiovasc Pharmacol
31:
292-298,
1998[ISI][Medline].
94.
Helmerhorst, FM,
Rosendaal FR,
and
Vandenbroucke JP.
Venous thromboembolism and the pill. The WHO technical report on cardiovascular disease and steroid hormone contraception: state-of-the-art.
Hum Reprod
13:
2981-2983,
1998
95.
Herrington, DM,
Braden GA,
Williams JK,
and
Morgan TM.
Endothelial-dependent coronary vasomotor responsiveness in postmenopausal women with and without estrogen replacement therapy.
Am J Cardiol
73:
951-952,
1994[ISI][Medline].
96.
Himber, J,
Missano B,
and
Kuhl H.
Lack of effect on the low density lipoprotein receptor in hamsters treated with 17-ethinyl estradiol.
Biochem Biophys Acta
1211:
359-363,
1994[ISI][Medline].
97.
Hodges, YK,
Richer JK,
Horwitz KB,
and
Horwitz LD.
Variant estrogen and progesterone receptor messages in human vascular smooth muscle.
Circulation
99:
2688-2693,
1999
98.
Hodges, YK,
Tung L,
Yan XD,
Graham JD,
Horwitz KB,
and
Horwitz LD.
Estrogen receptors and
. Prevelance of estrogen receptor
mRNA in human vascular smooth muscle and transcriptional effects.
Circulation
101:
1792-1798,
2000
99.
Holm, P,
Andersen HL,
Andersen MR,
Erhardsten E,
and
Stender S.
The direct antiatherogenic effect of estrogen is present, absent or reversed, depending on the state of the arterial endothelium. A time course study in cholesterol-clamped rabbits.
Circulation
100:
1727-1733,
1999
100.
Holm, P,
Korsgaard N,
Shalmi M,
Andersen HL,
Hougaard P,
Skouby SO,
and
Stender S.
Significant reduction of the antiatherogenic effect of estrogen by long-term inhibition of nitric oxide synthesis in cholesterol clamped rabbits.
J Clin Invest
100:
821-828,
1997
101.
Hong, MK,
Romm PA,
Reagan K,
Green CE,
and
Rackley CE.
Effects of estrogen replacement therapy on serum lipid values and angiographically defined coronary artery disease in postmenopausal women.
Am J Cardiol
69:
176-178,
1992[ISI][Medline].
102.
Hou, X,
Li JJ,
Chen W,
and
Li SA.
Estrogen-induced proto-oncogene and suppressor gene expression in the hamster kidney: significance for estrogen carcinogenesis.
Cancer Res
56:
2616-2620,
1996[Abstract].
103.
Hovarth, PM.
Sex steroids: physiology and metabolism.
In: Hormone Replacement Therapy, edited by Swartz DP.. Baltimore, MD: Williams and Wilkins, 1992, p. 1-16.
104.
Hulley, S,
Grady D,
Bush T,
Furberg C,
Herrington D,
Riggs B,
and
Vittinghoff E.
Randomized trial of estrogen plus progestin for secondary prevention of coronary heart disease in postmenopausal women.
JAMA
280:
605-613,
1998
105.
Hwang, SJ,
Ballantyne CM,
Sharrett R,
Smith LC,
Davis CE,
Gotto AM,
and
Boerwinkle E.
Circulating adhesion molecules VCAM-1, ICAM-1 and E-selectin in carotid atherosclerosis and Incident coronary heart disease cases. The atherosclerosis risk in communities (ARIC) study.
Circulation
96:
4219-4225,
1997
106.
Iademarco, MF,
McQuillan JJ,
Rosen GD,
and
Dean DC.
Characterization of the promoter for the vascular cell adhesion molecule-1 (VCAM-1).
J Biol Chem
267:
16323-16329,
1992
107.
Iafrati, MD,
Karas RH,
Aronovitz M,
Kim S,
Sullivan TR,
Lubahn DB,
O'Donnell TF,
Korach KS,
and
Mendelsohn ME.
Estrogen inhibits the vascular injury response in estrogen receptor deficient mice.
Nature Med
3:
545-548,
1997[ISI][Medline].
108.
Ignar-Trowbridge, DM,
Nelson KG,
Bidwell MC,
Curtis SW,
Washburn TF,
McLachlan JA,
and
Korach KS.
Coupling of dual signaling pathways: epidremal growth factor action involves estrogen receptor.
Proc Natl Acad Sci USA
89:
4658-4662,
1992[Abstract].
109.
Iguchi, M,
Takamura C,
Umekawa T,
Kurita T,
and
Kohri K.
Inhibitory effects of female sex hormones on urinary stone formation in rats.
Kidney Int
56:
479-485,
1999[ISI][Medline].
110.
Imthurn, B,
Rosselli M,
Jaeger AW,
Keller PJ,
and
Dubey RK.
Differential effects of hormone-replacement therapy on endogenous nitric oxide (nitrate/nitrite) levels in postmenopausal women substituted with 17-estradiol valerate and cyproterone acetate or medroxyprogesterone acetate.
J Clin Endocrinol Metab
82:
388-394,
1997
111.
Iruela-Arispe, L,
Gordon K,
Hugo C,
Duijvestijn AM,
Claffey KP,
Reilly M,
Couser WG,
Alpers CE,
and
Johnson RJ.
Participation of glomerular endothelial cells in the capillary repair of glomerulonephritis.
Am J Pathol
147:
1715-1727,
1995[Abstract].
112.
Jilma, B,
Hildebrqndt J,
Kapiotis S,
Wagner OF,
Kitzweger E,
Mullner C,
Monitzer B,
Krejcy K,
and
Eichler HG.
Effects of estradiol on circulating P-selectin.
J Clin Endocrinol Metab
81:
2350-2355,
1996[Abstract].
113.
Johns, A,
Frea AD,
Fraser W,
Korach KS,
and
Rubanyi GM.
Disruption of estrogen receptor gene prevents 17-estradiol-induced angiogenesis in transgenic mice.
Endocrinology
137:
4511-4513,
1996[Abstract].
114.
Joles, JA,
van Gloor H,
van der Horst ML,
van Tol A,
Weening JJ,
and
Koomans HA.
Ovariectomy decreases plasma triglyceride levels and both prevents and alleviates glomerular disease in uninephrectomized female analbuminemic rats.
J Am Soc Nephrol
7:
1189-1197,
1996[Abstract].
115.
Jun, SS,
Chen Z,
Pace MC,
and
Shaul PW.
Estrogen upregulates cyclooxygenase-1 gene expression in ovine fetal pulmonary artery endothelium.
J Clin Invest
102:
176-183,
1998
116.
Kagami, S,
Border WA,
Miller DE,
and
Noble NA.
Angiotensin II stimulates extracellular matrix protein synthesis through induction of transforming growth factor- expression in rat glomerular mesangial cells.
J Clin Invest
93:
2431-2437,
1994[ISI][Medline].
117.
Karas, RH,
Gauer EA,
Bieber HE,
Baur WE,
and
Mendelsohn ME.
Growth factor activation of the estrogen receptor in vascular cells occurs via a mitogen-activated protein kinase-independent pathway.
J Clin Invest
101:
2851-2861,
1998
118.
Karas, RH,
Hodgin JB,
Kwoun M,
Krege JH,
Aronovitz M,
Mackey W,
Gustafsson JA,
Korach KS,
Smithies O,
and
Mendelsohn ME.
Estrogen inhibits the vascular injury response in estrogen receptor beta-deficient female mice.
Proc Natl Acad Sci USA
96:
15133-15136,
1999
119.
Kashem, A,
Endoh M,
Yano N,
Yamaguci F,
Nomoto Y,
and
Sakai H.
Expression of inducible-NOS in human glomerulonephritis: the possible source infiltrating monocytes/macrophages.
Kidney Int
50:
392-399,
1996[ISI][Medline].
120.
Katzenellenbogen, BS,
and
Korach KS.
A new actor in the estrogen receptor dramaenter ER-
.
Endocrinology
138:
861-862,
1997
121.
Kauser, K,
Sonnenberg D,
Diel P,
and
Rubanyi GM.
Effect of 17beta-estradiol on cytokine-induced nitric oxide production in rat isolated aorta.
Br J Pharmacol
123:
1089-1096,
1998[Abstract].
122.
Keaney, JF,
Shwaery GT,
Xu A,
Nicolosi RJ,
Loscalzo J,
Foxall TL,
and
Vita JA.
17-Estradiol preserves endothelial vasodilator function and limits low-density lipoprotein oxidation in hypercholesterolemic swine.
Circulation
89:
2251-2259,
1994[Abstract].
123.
Kim, HP,
Lee JY,
Jeong JK,
Base SW,
Lee HK,
and
Jo I.
Nongenomic stimulation of nitric oxide release by estrogen is mediated by estrogen receptor alpha localized in caveolae.
Biochem Biophy Res Commun
263:
257-262,
1999[ISI][Medline].
124.
Kim-Schulze, S,
Lowe WL, Jr,
and
Schnaper W.
Estrogen stimulates delayed mitogen-activated protein kinase activity in human endothelial cells via an autocrine loop that involves basic fibroblast growth factor.
Circulation
98:
413-421,
1998
125.
Kirkman, H.
Autonomous derivatives of estrogen-induced renal carcinomas, and spontaneous renal tumors in Syrian hamsters.
Cancer Res
34:
2728-2744,
1974[ISI][Medline].
126.
Kitazawa, T,
Hamada E,
Kitazawa K,
and
Gaznabi AKM
Non-genomic mechanism of 17-oestradiol-induced inhibition of contraction in mammalian vascular smooth muscle.
J Physiol (Lond)
499:
497-511,
1997[Abstract].
127.
Koh, KK,
Blum A,
Hathaway L,
Mincemoyer R,
Csako G,
Waclawiw MA,
Panza JA,
and
Cannon RO, III.
Vascular effects of estrogen and vitamin E therapies in postmenopausal woomen.
Circulation
100:
1851-1857,
1999
128.
Koh, KK,
Mincemoyer R,
Sui MN,
Csako G,
Pucino F,
Guetta V,
Waclawiw M,
and
Cannon RO, III.
Effects of hormone-replacement therapy on fibrinolysis in postmenopausal women.
N Engl J Med
336:
683-690,
1997
129.
Kolodgie, FD,
Jacob A,
Wilson PS,
Carlson GC,
Farb A,
Verma A,
and
Virmani R.
Estradiol attenuates directed migration of vascular smooth muscle cells in vitro.
Am J Pathol
148:
969-976,
1996[Abstract].
130.
Korach, KS.
Insights from the study of animals lacking functional estrogen receptor.
Science
266:
1524-1527,
1994[ISI][Medline].
131.
Korach, KS,
Couse JF,
Curtis SW,
Washburn TF,
Lindzey J,
Kimbro KS,
Eddy EM,
Migliaccio S,
Snedeker SM,
Lubahn DB,
Schomberg DW,
and
Smith EP.
Estrogen receptor gene disruption: molecular characterization and experimental and clinical phenotypes.
Recent Prog Horm Res
51:
159-188,
1996[ISI][Medline].
132.
Krasinski, K,
Spyridopoulos S,
Asahara T,
van der Zee R,
Inser JM,
and
Losordo DW.
Estradiol accelerates functional endothelial recovery after arterial injury.
Circulation
95:
1768-1772,
1997
133.
Kuiper, GG,
Carlsson MB,
Grandien K,
Enmark V,
Haggblad J,
Nilsson S,
and
Gustafsson JA.
Comparison of the ligand binding specificity and transcript tissue distribution of estrogen receptors and
.
Endocrinology
138:
863-870,
1997
134.
Kuiper, GG,
Enmark E,
Huikko-Pelto M,
Nilsson S,
and
Gustafsson JA.
Cloning of a novel receptor expressed in rat prostate and ovary.
Proc Nat Acad Sci USA
93:
5925-5930,
1996
135.
Kuiper, GGJM,
Lemmen JG,
Carlsson B,
Corton JC,
Safe SH,
van der Saag PT,
van der Berg B,
and
Gustafsson JA.
Interaction of estrogenic chemicals and phytoestrogens with estrogen receptor .
Endocrinology
139:
4252-4263,
1998
136.
Kushwaha, RS,
Guntupalli B,
Jackson EM,
and
McGill HC, Jr.
Effect of estrogen and progesterone on the expression of hepatic and extrahepatic sterol 27-hydroxylase in baboons (Papio sp).
Arterioscler Thromb Vasc Biol
16:
1088-1094,
1996
137.
Kwan, G,
Neugarten J,
Sherman M,
Ding Q,
Fotadar U,
Lei J,
and
Silbiger S.
Effects of sex hormones on mesangial cell proliferation and collagen synthesis.
Kidney Int
50:
1173-1179,
1996[ISI][Medline].
138.
Laitinen, M,
Zachary I,
Breier G,
Pakkanen T,
Hakkinen T,
Luoma J,
Abedi H,
Risau W,
Soma M,
Laakso M,
Martin JF,
and
Yla-Herttuala S.
VEGF gene transfer reduces intimal thickening via increased production of nitric oxide in carotid arteries.
Hum Gene Ther
8:
1737-1744,
1997[ISI][Medline].
139.
Lantin-Hermoso, RL,
Rosenfeld CR,
Yuhanna IS,
German Z,
Chen Z,
and
Shaul PW.
Estrogen acutely stimulates nitric oxide synthase activity in fetal pulmonary artery endothelium.
Am J Physiol Lung Cell Mol Physiol
273:
L119-L126,
1997
140.
Lee, LK,
Meyer TW,
Pollock AS,
and
Lovett DH.
Endothelial cell injury initiates glomerular sclerosis in the rat remnant kidney.
J Clin Invest
96:
953-964,
1995[ISI][Medline].
141.
Lei, J,
Silbiger S,
Ziyadeh FN,
and
Neugarten J.
Serum-stimulated 1 type IV collagen gene transcription is mediated by TGF-
and inhibited by estradiol.
Am J Physiol Renal Physiol
274:
F252-F258,
1998
142.
Lengsfeld, M,
Morano I,
Ganten U,
Ganten D,
and
Riggs JC.
Gonadectomy and hormonal replacement changes systolic blood pressure and ventricular myosin isoenzyme pattern of spontaneously hypertensive rats.
Circ Res
63:
1090-1094,
1988[Abstract].
143.
Lerner, DJ,
and
Kannel WB.
Patterns of coronary heart disease morbidity and mortality in the sexes: a 26-year follow-up of the Framingham population.
Am Heart J
111:
383-390,
1986[ISI][Medline].
144.
Levine, RL,
Chen SJ,
Durand J,
Chen YF,
and
Oparil S.
Medroxyprogesterone attenuates estrogen-mediated inhibition of neointima formation after balloon injury of the rat carotid artery.
Circulation
94:
2221-2227,
1996
145.
Li, G,
Chen YF,
Greene GL,
Oparil S,
and
Thompson JA.
Estrogen inhibits vascular smooth muscle cell-dependent adventitial fibroblast migration in vitro.
Circulation
100:
1639-1645,
1999
146.
Li, JJ,
Hou X,
Banerjee SK,
Liao DZJ,
Maggouta F,
Norris JS,
and
Li SA.
Overexpression and amplication of c-myc in Syrian hamster kidney during estrogen carcinogenesis: a probable critical role in neoplastic transformation.
Cancer Res
59:
2340-2346,
1999
147.
Li, SA,
Liao DZ,
Yazlovitskaya EM,
Pantazis CG,
and
Li JJ.
Induction of cathepsin D protein during estrogen carcinogenesis: possible role in estrogen-mediated kidney tubular cell damage.
Carcinogenesis
18:
1375-1380,
1997[Abstract].
148.
Liehr, JG,
and
Ricci MJ.
4-Hydroxylation of estrogens as marker of human mammary tumors.
Proc Natl Acad Sci USA
93:
3294-3296,
1996
149.
Linder, V,
Kim SK,
Kara RH,
Kuiper GGJM,
Gustafsson JA,
and
Mendelsohn ME.
Increased expression of estrogen receptor B mRNA in male blood vessels after vascular injury.
Circ Res.
83:
224-229,
1998
150.
Lindheim, SR,
Legro RS,
Bernstein L,
Stanczyck FZ,
Vijod MA,
Presser SC,
and
Lobo RA.
Behavioral stress responses in premenopausal and post-menopausal women and the effects of estrogen.
Am J Obstet Gynecol
167:
183-1836,
1992.
151.
Liu, D,
and
Bachmann KA.
An investigation of the relationship between estrogen, estrogen metabolites and blood cholesterol levels in ovariectomized rats.
J Pharmacol Exp Therap
286:
561-568,
1998
152.
Lobo, RA.
Estrogen and the risk of coagulopathy.
Am J Med
92:
283-285,
1992[ISI][Medline].
153.
Lou, H,
Kodama T,
Zhao J,
Maurice P,
Wang YN,
Katz N,
and
Foegh ML.
Inhibition of transplant coronary arteriosclerosis in rabbits by chronic estradiol treatment is associated with abolition of MHC class II antigen expression.
Circulation
94:
3355-3361,
1996
154.
Lou, H,
Martin MB,
Stoica A,
Ramwell PW,
and
Foegh ML.
Upregulation of estrogen receptor- expression in rabbit cardiac allograft.
Circ Res
83:
947-951,
1998
155.
Lou, H,
Ramwell PW,
and
Foegh ML.
Estradiol 17 represses insulin-like growth factor I receptor expression in smooth muscle cells from rabbit cardiac recipients.
Transplantation
66:
419-426,
1998[ISI][Medline].
156.
Lou, H,
Zhao Y,
Delafontaine P,
Kodama T,
Katz NM,
Ramwell P,
and
Foegh ML.
Estrogen effects on insulin-like growth factor-I (IGF-I) induced cell proliferation and IGF-I expression in native and allograft vessels.
Circulation
96:
927-933,
1997
157.
Mäkela, S,
Savolainen H,
Aavik E,
Myllärniemi M,
Strauss L,
Taskinen E,
Gustafsson JA,
and
Häyry P.
Differentiation between vasculoprotective and uterotrophic effects of ligands with different binding affinities to estrogen receptors alpha and beta.
Proc Natl Acad Sci USA
96:
7077-7082,
1999
158.
Maltepe, E,
Schmidt JV,
Baunoch D,
Bradfield CA,
and
Simon MC.
Abnormal angiogenesis and responses to glucose and oxygen deprivation in mice lacking the protein ARNT.
Nature
386:
403-407,
1997[ISI][Medline].
159.
Manns, BJ,
Burgess ED,
Hyndman ME,
Parsons HG,
Schaefer JP,
and
Scott-Douglas NW.
Hyperhomocyst(e)inemia and the prevelance of atherosclerotic vascular disease in patients with end-stage renal disease.
Am J Kidney Dis
34:
669-677,
1999[ISI][Medline].
160.
Markaverich, BM,
and
Gregory RR.
Preliminary characterization and partial purification of rat uterine nuclear type II binding sites.
Biochem Biophys Res Commun
177:
1283-1290,
1991[ISI][Medline].
161.
Markaverich, BM,
Roberts RR,
Alejandro MA,
Johnson GA,
Middleditch BS,
and
Clark JH.
Bioflavonoid interaction with rat uterine type II binding sites and cell growth inhibition.
J Steroid Biochem
30:
71-78,
1988[ISI][Medline].
162.
Markides, CSA,
Roy D,
and
Liehr JG.
Concentration dependence of prooxidant and antioxidant properties of catechol estrogens.
Arch Biochem Biophys
360:
105-112,
1998[ISI][Medline].
163.
Martin, C,
Barturen K,
Martinez R,
Lacort M,
and
Ruiz-Larrea MB.
In vitro inhibition by estrogens of the oxidative modifications of human lipoproteins.
J Physiol Biochem
54:
195-202,
1998[ISI][Medline].
164.
Martucci, CP,
and
Fishmann J.
P450 enzyme of estrogen metabolism.
Pharmacol Ther
57:
237-257,
1993[ISI][Medline].
165.
Masuzaki, H,
Jingami H,
Yamamoto T,
and
Nakao K.
Effects of estradiol on very low density lipoprotein receptor mRNA levels in rabbit heart.
FEBS Lett
347:
211-214,
1994[ISI][Medline].
166.
Mendelsohn, ME,
and
Karas RH.
The protective effects of estrogen on the cardiovascular system.
N Engl J Med
340:
1801-1811,
1999
167.
Messmer, UK,
Briner VA,
and
Pfeilschifter J.
Tumor necrosis factor-alpha and lipopolysaccharide induce apoptotic cell death in bovine glomerular endothelial cells.
Kidney Int
55:
2322-2337,
1999[ISI][Medline].
168.
Migliaccio, A,
Domenico M,
Di Castoria G,
de Falco A,
Bontempo P,
Nola E,
and
Auricchio F.
Tyrosine kinase/p21ras/MAP-kinase pathway activation by estradiol-receptor complex in MCF-7 cells.
EMBO J
15:
1292-1300,
1996[Abstract].
169.
Mikkola, T,
Turunen P,
Avela K,
Orpana A,
Viinikka L,
and
Ylikorkala O.
17-Estradiol stimulates prostacyclin, but not endothelin-1, production in human vascular endothelial cells.
J Clin Endocrinol Metab
80:
1832-1836,
1995[Abstract].
170.
Miller, JA,
Anacta LA,
and
Cattran DC.
Impact of gender on the renal response to angiotensin II.
Kidney Int
55:
278-285,
1999[ISI][Medline].
171.
Miller, L,
Alley EW,
Murphy WJ,
Russell SW,
and
Hunt JS.
Progesterone inhibits inducible nitric oxide synthase gene expression and nitric oxide production in murine macrophages.
J Leukoc Biol
59:
442-450,
1996[Abstract].
172.
Montano, MM,
Chang W,
and
Katzenellenbogen BS.
An estrogen receptor-selective corepressor: cloning and characterization (Abstract).
Endocrinology
98:
96,
1998.
173.
Morales, DE,
McGowan KA,
Grant DS,
Maheshwari S,
Bhartiya D,
Cid MC,
Kleinman HK,
and
Schnaper HW.
Estrogen promotes angiogenic activity in human umbilical vein endothelial cells in vitro and in a murine model.
Circulation
91:
755-763,
1995
174.
Moran, CS,
Campbell JH,
and
Campbell GR.
Human leukemia inhibitory factor upregulates LDL receptors on liver cells and decreases serum cholesterol in the cholesterol-fed rabbits.
Arterioscler Thromb Vasc Biol
17:
1267-1273,
1997
175.
Moran, CS,
Campbell JH,
Simmons DL,
and
Campbell GR.
Human leukemia inhibitory factor inhibits development of experimental atherosclerosis.
Arterioscler Thromb Vasc Biol
14:
1356-1363,
1994[Abstract].
176.
Morey, AK,
Pedram A,
Razandi M,
Prins BA,
Hu RM,
Biesiada E,
and
Levin ER.
Estrogen and progesterone inhibit vascular smooth muscle proliferation.
Endocrinology
138:
3330-3339,
1997
177.
Morey, AK,
Razandi M,
Pedram A,
Hu RM,
Prins BA,
and
Levin ER.
Oestrogen and progesterone inhibit the stimulated production of endothelin-1.
Biochem J
330:
1097-1105,
1998[ISI][Medline].
178.
Mosselman, S,
Polman J,
and
Dijkema R.
ER-: identification and characterization of a novel human estrogen receptor.
FEBS Lett
392:
49-53,
1996[ISI][Medline].
179.
Motomura, N,
Lou H,
Hong M,
Tsutsumi Y,
Mayumi T,
and
Forgh M.
Local administration of estrogen inhibits transplant arteriosclerosis in rat aorta accelerated by tropical exposure to IGF-1.
Transplant Proc
29:
1118-1120,
1997[ISI][Medline].
180.
Muller, V,
Szabo A,
Viklicky O,
Gaul I,
Portl S,
Philipp T,
and
Heemann UW.
Sex hormones and gender-related differences: their influence on chronic renal allograft rejection.
Kidney Int
55:
2011-2020,
1999[ISI][Medline].
181.
Mulroney, SE,
Woda C,
Johnson M,
and
Pesce C.
Gender differences in renal growth and function after uninephrectomy in adult rats.
Kidney Int
56:
944-953,
1999[ISI][Medline].
182.
Munger, K,
and
Baylis C.
Sex differences in renal hemodynamics in rats.
Am J Physiol Renal Fluid Electrolyte Physiol
254:
F223-F231,
1988
183.
Nabekura, J,
Oomura Y,
Minami T,
Mizuno Y,
and
Fukuda A.
Mechanism of the rapid effect of 17beta-estradiol on medial amygdala neurons.
Science
233:
226-228,
1986[ISI][Medline].
184.
Nabulsi, AA,
Folsom AR,
White A,
Patsch W,
Heiss G,
Wu KK,
and
Syzklo M.
For the atherosclerosis risk in communities study investigators: association of hormone-replacement therapy with various cardiovascular risk factors in postmenopausal women.
N Engl J Med
328:
1069-1075,
1993
185.
Nakai, K,
Itoh C,
Hotta K,
Itoh T,
Yoshizumi M,
and
Hiramori K.
Estradiol-17 regulates the induction of VCAM-1 mRNA expression by interleukin-1
in human umbilical vein endothelial cells.
Life Sci
54:
221-227,
1994.
186.
Nakajima, T,
Kitazawa T,
Hamada E,
Hazama H,
Omata M,
and
Kurachi Y.
17Beta-estradiol inhibits voltage-dependent L-type Ca2+ currents in aortic smooth muscle cells.
Eur J Pharmacol
294:
625-635,
1995[ISI][Medline].
187.
Nakano, Y,
Oshima T,
Matsuura H,
Kajiyama G,
and
Kambe M.
Effect of 17beta-estradiol on inhibition of platelet aggregation in vitro is mediated by an increase in NO synthesis.
Arterioscler Thromb Vasc Biol
18:
961-967,
1998
188.
Narita, I,
Border WA,
Kettler M,
and
Noble NA.
Nitric oxide mediates immunologic injury to kidney mesangium in experimental glomerulonephritis.
Lab Invest
72:
17-24,
1995[ISI][Medline].
189.
Naschimento, CAD,
Kauser K,
and
Rubanyi G.
Effect of 17-estradiol in hypercholesterolemic rabbits with sever endothelial dysfunction.
Am J Physiol Heart Circ Physiol
276:
H1788-H1794,
1999
190.
Nathan, L,
Pervin S,
Singh R,
Rosenfeld M,
and
Chaudhuri G.
Estradiol inhibits leukocyte adhesion and transendothelial migration in rabbits in vivo. Possible mechanisms for gender differences in atherosclerosis.
Circ Res
85:
377-385,
1999
191.
Negree-Salvayre, A,
Pieraggi MT,
Mabile L,
and
Salvayre R.
Protective effect of 17beta-estradiol against cytotoxicity of minimally oxidized LDL to cultured bovine aortic endothelial cells.
Atherosclerosis
99:
207-217,
1993[ISI][Medline].
192.
Neugarten, J,
Acharya A,
and
Silbiger SR.
Effect of gender on the progression of nondiabetic renal disease: a meta-analysis.
J Am Soc Nephrol
11:
319-329,
2000
193.
Neugarten, J,
Ding Q,
Friedman A,
Lei J,
and
Silbiger S.
Sex hormones and renal nitric oxide synthases.
J Am Soc Nephrol
8:
1240-1246,
1997[Abstract].
194.
Neugarten, J,
Ghossein C,
and
Silbiger S.
Estradiol inhibits mesangial cell mediated oxidation of low-density lipoprotein.
J Lab Clin Med
126:
385-391,
1995[ISI][Medline].
195.
Neugarten, J,
Jei J,
Acharya S,
and
Silbiger S.
Estradiol reverses AII- and endothelin-stimulated mesangial cell COL4A1 gene transcription by antagonizing autocrine TGF-1 (Abstract).
J Am Soc Nephrol
10:
577A,
1999.
196.
Neugarten, J,
Medve I,
Lei J,
and
Silbiger SR.
Estradiol suppresses mesangial cell type I collagen synthesis via activation of the MAP kinase cascade.
Am J Physiol Renal Physiol
277:
F875-F881,
1999
197.
New, G,
Timmins KL,
Auffy SJ,
Tran BT,
O'Brien RC,
Harper RW,
and
Meredith IT.
Long-term estrogen therapy improves vascular function in male to female transsexuals.
J Am Coll Cardiol
29:
1437-1444,
1997[ISI][Medline].
198.
Nickenig, G,
Baumer AT,
Grohe C,
Kahlert S,
Strehlow K,
Rosenkranz S,
Stäblein A,
Beckers F,
Jos Smits FM,
Daemen MJAP,
Vetter H,
and
Böhm M.
Estrogen modulates AT1 receptor gene expression in vitro and in vivo.
Circulation
97:
2197-2201,
1998
199.
Nishigaki, I,
Sasaguri Y,
and
Yagi K.
Anti-proliferative effect of 2-methoxyestradiol on cultured smooth muscle cells from rabbit aorta.
Atherosclerosis
113:
167-170,
1995[ISI][Medline].
200.
Node K, Kitakaze M, Kosaka H, Minamino T, Funaya H, and Hori M. Amelioration of ischemia- and reperfusion-induced myocardial
injury by 17-estradiol: role of nitric oxide and calcium-activated
potassium channels. Circulation 96: 1953-1963.
201.
Okada, M,
Suzuki A,
Mizuno K,
Asada Y,
Ino Y,
Kuwayama T,
Tamakoshi K,
Mizutani S,
and
Tomoda Y.
Effects of 17-estradiol and progesterone on migration of human monocytic THP-1 cells stimulated by minimally oxidized low density lipoproteins in vitro.
Cardiovasc Res
34:
529-535,
1997[ISI][Medline].
202.
Onoe, Y,
Miyaura C,
Ohta H,
Nozawa S,
and
Suda T.
Expression of estrogen receptor in rat bone.
Endocrinology
138:
4509-4512,
1997
203.
Oparil, S.
Hormones and vasoprotection.
Hypertension
33:
170-176,
1999
204.
Oparil, S,
Levine RL,
Chen SJ,
Durand J,
and
Chen YF.
Sexually dimorphic response of the balloon-injured rat carotid artery to hormone treatment.
Circulation
95:
1301-1307,
1997
205.
Oparil, S,
Levine RL,
and
Chen YF.
Sex hormones and the vasculature.
In: Endocrinology of the Vasculature, edited by Sowers JR,
and Walsh M.. Totwa, NJ: Humana, 1996, p. 225-237.
206.
Ostendorf, T,
Kunter U,
Eitner F,
Loos A,
Regele H,
Kerjaschki D,
Henninger DD,
Janjic N,
and
Floege J.
VEGF (165) mediates glomerular endothelial repair.
J Clin Invest
104:
913-923,
1999
207.
Ostrowski, NL,
Young WS, III,
and
Lolait SJ.
Estrogen increases renal oxytocin receptor gene expression.
Endocrinology
136:
1801-1804,
1995[Abstract].
208.
Paech, K,
Webb P,
Kuiper GG,
Nilsson S,
Gustafsson JA,
Kushner PJ,
and
Scanlan TS.
Differential ligand activation of estrogen receptor ERalpha and ERbeta at AP1 sites.
Science
277:
1508-1510,
1997
209.
Pappas, TC,
Gametchu B,
and
Watson CS.
Membrane estrogen receptors identified by multiple antibody labeling and impeded-ligand binding.
FASEB J
9:
404-410,
1995
210.
Parini, P,
Angelin B,
and
Rudling M.
Importance of estrogen receptors in hepatic LDL receptor regulation.
Arterioscler Thromb Vasc Biol
17:
1800-1805,
1997
211.
Parthasarathy, S,
Printz DJ,
Boyd D,
Joy L,
and
Steinberg D.
Macrophage oxidation of low density liporpotein generates a modified form recognized by the scavenger receptor.
Arteriosclerosis
6:
505-510,
1986[Abstract].
212.
Pasqualini, C,
Leviel V,
Guibert B,
Faucon-Biguet N,
and
Kerdelhui B.
Inhibitory action of acute estradiol treatment on the activity and quantity of tyrosine hydroxylase in the median eminence of ovariectomized rats.
J Neuroendocrinol
3:
575-580,
1991[ISI].
213.
Pennie, WD,
Aldridge TC,
and
Brooks AN.
Differential activation by xenoestrogens of ER alpha and ER beta when linked to different response elements.
J Endocrinol
158:
R11-R14,
1998[Abstract].
214.
Pervin, S,
Singh R,
Roscnfeld ME,
Navab M,
Chaudhuri G,
and
Nathan L.
Estradiol suppresses MCP-1 expression in vivo: implications for athero-sclerosis.
Arterioscler Thromb Vasc Biol
18:
1575-1582,
1998
215.
Petersen, DN,
Tkalcevic GT,
Koza-Taylor PH,
Turi TG,
and
Brown TA.
Identification of estrogen receptor S2, a functional variant of estrogen receptor beta expressed in normal rat tissues.
Endocrinology
139:
1082-1092,
1998
216.
Philips, A,
Chalbos D,
and
Rochefort H.
Estradiol increases and anti-estrogens antagonize the growth factor induced activator protein-1 activity in MCF7 breast cancer cells without affecting c-fos and c-jun synthesis.
J Biol Chem
268:
14103-14108,
1993
217.
Pietras, RJ,
and
Szego CM.
Endometrial cell calcium and oestradiol action.
Nature
253:
357-359,
1975[ISI][Medline].
218.
Proudler, AJ,
Ahmed AI,
Crook D,
Fogelman I,
Rymer JM,
and
Stevenson JC.
Hormone replacement therapy and serum angiotensin-converting enzyme activity in postmenopausal women.
Lancet
346:
89-90,
1995[ISI][Medline].
219.
Quintao, ECR,
Nakandakare E,
Oliveira HC,
Rocha JC,
Garcia PC,
and
de Melo NR.
Oral estradiol-17 raises the level of plasma high-density lipoprotein in menopausal women by slowing down its clearance rate.
Acta Endocrinol
125:
657-661,
1991[ISI][Medline].
220.
Reckelhoff, JF,
Hennington BS,
Moore AG,
Blanchard EJ,
and
Cameron J.
Gender differences in the renal nitric oxide (NO) system: dissociation between expression of endothelial NO synthase and renal hemodynamic response to NO synthase inhibition.
Am J Hypertens
11:
97-104,
1998[ISI][Medline].
221.
Reinhart, KC,
Dubey RK,
Mummery CL,
van Rooijen M,
Keller PJ,
and
Rosselli M.
Synthesis and regulation pf leukaemia inhibitory factor in cultured bovine oviduct cells by hormones.
Mol Hum Reprod
4:
301-308,
1998[Abstract].
222.
Reis, SE,
Bhoopalam V,
Zell KA,
Counihan PJ,
Smith AJC,
Pham S,
and
Murali S.
Conjugated estrogens acutely abolish abnormal cold-induced coronary vasoconstriction in male cardiac allografts.
Circulation
97:
23-25,
1998
223.
Rifici, VA,
and
Khachadurian AK.
The inhibition of low-density lipoprotein oxidation by 17-estradiol.
Metabolism
41:
1110-1114,
1992[ISI][Medline].
224.
Roque, M,
Heras M,
Roig E,
Masotti M,
Rigol M,
Betriu A,
Balasch J,
and
Sanz G.
Short-term effects of transdermal estrogen replacement therapy on coronary vascular reactivity in postmenopausal women with angia pectoris and normal results on coronary angiograms.
J Am Coll Cardiol
31:
139-143,
1998[ISI][Medline].
225.
Rosenberg, L,
Hennekens CH,
Rosner B,
Belanger C,
Rothman KJ,
and
Spiter FE.
Early menopause and risk of myocardial infarction.
Am J Obstet Gynecol
139:
47-51,
1981[ISI][Medline].
226.
Rosenmann, E,
Yanko L,
and
Cohen AM.
Female sex hormone and nephropathy in cohen diabetes rat (genetically selected sucrose fed).
Horm Metab Res
16:
11-16,
1984[ISI][Medline].
227.
Ross, R.
The pathogenesis of atherosclerosis: a perspective for the 1990s.
Nature
362:
801-809,
1993[ISI][Medline].
228.
Rosselli, M,
Imthurn B,
Keller PJ,
Jackson EK,
and
Dubey RK.
Circulating nitric oxide (nitrite/nitrate) levels in postmenopausal women substituted with 17-estradiol and norethisterone acetate: a two year follow-up study.
Hypertension
25:
848-853,
1995
229.
Rosselli, M,
Keller PJ,
Kern F,
Hahn AWA,
and
Dubey RK.
Estradiol inhibits mitogen induced proliferation and migration of human aortic smooth muscle cells: implications for cardiovascular disease in women (Abstract).
Circulation
90:
I-87,
1994.
230.
Rosselli, M,
Reinhart K,
Imthurn B,
Keller PJ,
and
Dubey RK.
Cellular and biochemical mechanisms by which environmental estrogens may influence the reproduction function.
Hum Reprod Update
6:
332-350,
2000
231.
Rowlands, JC,
and
Gustafsson JA.
Aryl hydrocarbon receptor-mediated signal transduction.
Crit Rev Toxicol
27:
109-134,
1997[ISI][Medline].
232.
Rubanyi, GM,
Freay AD,
Kauser K,
Sukovich D,
Burton G,
Lubah DB,
Couse JF,
Curtis SW,
and
Korach KS.
Vascular estrogen receptors and endothelium-derived nitric oxide production in the mouse aorta: gender difference and effect of estrogen receptor gene disruption.
J Clin Invest
99:
2429-2437,
1997
233.
Ruehlmann, DO,
Steinert JR,
Valverde MA,
Jacob R,
and
Mann GE.
Environmental estrogenic pollutants induce acute vascular relaxation by inhibiting L-type Ca2+ channels in smmoth muscle cells.
FASEB J
12:
613-619,
1998
234.
Rusko, J,
Li L,
and
van Breemen C.
17-Estradiol stimulation of endothelial K+ channels.
Biochem Biophys Res Commun
214:
367-372,
1995[ISI][Medline].
235.
Russell, KS,
Hayes MP,
Sinha D,
Clerisme E,
and
Bender JR.
Human vascular endothelial cells contain membrane binding sites for estradiol which mediate rapid intracellular signaling.
Proc Natl Acad Sci USA
97:
5930-5935,
2000
236.
Sack, MN,
Rader DJ,
and
Cannon RO.
Oestrogen and inhibition of oxidation of low-density lipoproteins in postmenopausal women.
Lancet
343:
269-270,
1994[ISI][Medline].
237.
Safe, SH.
Modulation of gene expression and endocrine response pathways by 2,3,7,8-tetrachlorodibenzo-p-dioxin and related compounds.
Pharmacol Ther
67:
247-281,
1995[ISI][Medline].
238.
Saito, S,
Aras RS,
Lou H,
Ramwell PW,
and
Foegh ML.
Effects of estrogen on nitric oxide synthase expression in rat aorta allograft and smooth muscle cells.
J Heart Lung Transplant
18:
937-945,
1999[ISI][Medline].
239.
Saito, S,
Lou H,
Ramwell PW,
and
Foegh ML.
Growth factors and transplant vascular disease.
Immunol Rev
12:
96-109,
1998.
240.
Sakemi, T,
Tomiyoshi Y,
Miyazono M,
and
Ikeda Y.
Estrogen replacement therapy with its physiological dose does not eliminate the aggravating effect of ovariectomy on glomerular injury in hypercholesterolemic female Imai rats.
Nephron
80:
324-330,
1998[ISI][Medline].
241.
Salomaa, V,
Rasi V,
Pekkanen J,
Vahtera E,
Jauhiainen M,
Vartiainen E,
Ehnholm C,
Tuomilehto J,
and
Myllyla G.
Association of hormone replacement therapy vvith hemostatic and other cardiovascular risk factors: the FINRISK Hemostasis Study.
Arterioscler Thromb Vasc BioI
15:
1549-1555,
1995
242.
Schmidt, JV,
and
Bradfield CA.
Ah receptor signaling pathways.
Annu Rev Cell Dev Biol
12:
55-89,
1996[ISI][Medline].
243.
Schnaper, HW,
McGowan KA,
Kim-Schulze S,
and
Cid MC.
Oestrogen and endothelial cell angiogenic activity.
Clin Exp Pharmacol Physiol
23:
261-250,
1996.
244.
Schunkert, H,
Danser AHJ,
Hense HW,
Frans FHM,
Kürzinger S,
and
Riegger GAJ
Effects of estrogen replacement therapy on the renin-angiotensin system in postmenopausal women.
Circulation
95:
39-45,
1997
245.
Schwenke, DC.
Aging, menopause and free radicals.
Semin Reprod Endocrinol
16:
281-308,
1998[ISI][Medline].
246.
Seeger, H,
Mueck AO,
and
Lippert TH.
Effect of estradiol metabolites on prostacyclin synthesis in human endothelial cell cultures.
Life Sci
65:
167-170,
1999.
247.
Selzman, CH,
Gaynor JS,
Turner AS,
Johnson SM,
Horwitz LD,
Whitehill TA,
and
Harken AH.
Ovarian ablation alone promotes aortic hyperplasia and accumulation of fibroblast growth factor.
Circulation
98:
2049-2054,
1998
248.
Selzman, CH,
Gaynor JS,
Turner AS,
Whitehall TA,
Horwitz LD,
and
Harken AH.
Estrogen replacement inhibits hyperplasia and the accumulation and effects of transforming growth factor beta 1.
J Surg Res
80:
380-385,
1998[ISI][Medline].
249.
Sharkey, LC,
Holycross BJ,
Park S,
Shiry LJ,
Hoepf TM,
McCune SA,
and
Radin MJ.
Effect of ovariectomy and estrogen replacement on cardiovascular disease in heart failure SHHF/Mac-facp rats.
J Mol Cell Cardiol
31:
1527-1537,
1999[ISI][Medline].
250.
Sharma, K,
and
Ziyadeh FN.
The emerging role of transforming growth factor- in kidney diseases.
Am J Physiol Renal Fluid Electrolyte Physiol
266:
F829-F842,
1994
251.
Shibata, H,
Spencer TE,
Onate SA,
Jenster G,
Tsai GY,
Tsai MJ,
and
O'Malley BW.
Role of co-activators and co-repressors in the mechanism of steroid/thyroid receptor action.
Recent Prog Horm Res
52:
141-165,
1997[ISI][Medline].
252.
Shwaery, GT,
Vita JA,
and
Keaney FR, Jr.
Antioxidant protection of LDL by physiological concentrations of 17-estradiol Requirement for estradiol modification.
Circulation
95:
1378-1385,
1997
253.
Silbiger, S,
Lei J,
and
Neugarten J.
Estradiol suppresses type I collagen synthesis by mesangial cells via activation of AP-1.
Kidney Int
55:
1268-1276,
1998[ISI].
254.
Silbiger, S,
Lei J,
Ziyadeh FN,
and
Neugarten J.
Estradiol reverses TGF-1 stimulated type IV collagen gene transcription in murine mesangial cells.
Am J Physiol Renal Physiol
274:
F1113-F1118,
1998
255.
Silbiger, S,
and
Neugarten J.
The impact of gender on the progression of chronic renal disease.
Am J Kidney Dis
25:
515-533,
1995[ISI][Medline].
256.
Simoncini, T,
De Caterina R,
and
Genazzani AR.
Selective estrogen receptor modulators: different actions on vascular cell adhesion molecule-1 (VCAM-1) expression in human endothelial cells.
J Clin Endocrinol Metab
84:
815-818,
1999
257.
Singhal, PC,
Reddy K,
Franki N,
Sanwal V,
Kapasi A,
Gibbons N,
Mattana J,
and
Valderrama E.
Age and sex medulate renal expression of SGP-2 and transglutaminase and apoptosis of splenocytes, thymocytes, and macrophages.
J Investig Med
45:
567-575,
1997[ISI][Medline].
258.
Spyridopoulos, I,
Sullivan AB,
Kearney M,
Isner JM,
and
Losordo DW.
Estrogen-receptor-mediated inhibition of human endothelial cell apoptosis. Estradiol as a survival factor.
Circulation
95:
1505-1514,
1997
259.
Srivastava, RAK,
Baumann D,
and
Schonfeld G.
In vivo regulation of low-density lipoprotein receptors by estrogen differs at the post-transcriptional level in rat and mouse.
Eur J Biochem
216:
527-538,
1993[Abstract].
260.
Srivastava, RA,
Srivastava N,
Averna M,
Lin RC,
Korach KS,
Lubahn DB,
and
Schonfeld G.
Estrogen up-regulates apolipoprotein E (Apo E) gene expression by increasing ApoE mRNA in the translating pool via the estrogen receptor alpha-mediated pathway.
J Biol Chem
272:
33360-33366,
1997
261.
Stampfer, MJ,
and
Colditz GA.
Estrogen replacement therapy and coronary heart disease: a quantitative assessment of the epidemiologic evidence.
Prev Med
20:
47-63,
1991[ISI][Medline].
262.
Stefano, GB,
Prevot V,
Beauvillain JC,
Cadet P,
Fimiani C,
Welters I,
Fricchione GL,
Breton C,
Lassalle P,
Salzet M,
and
Bilfinger TV.
Cell surface estrogen receptors mediate calcium-dependent nitric oxide release in human endothelia.
Circulation
101:
1594-1597,
2000
263.
Stein, B,
and
Yang MY.
Repression of the interleukin-6 promoter by estrogen receptor is mediated by NF- and C/EBP beta.
Mol Cell Biol
15:
4971-4979,
1995[Abstract].
264.
Stevenson, FT,
Wheeldon CM,
Gades MD,
Kaysen GA,
Stern JS,
and
van Gloor H.
Estrogen worsens incipient hypertriglyceridemic glomerular injury in the obese Zucker rats.
Kidney Int
57:
1927-1935,
2000[ISI][Medline].
265.
Stewart, JH.
End-stage renal failure appears earlier in men than in women with polycystic kidney disease.
Am J Kidney Dis
24:
181-183,
1994[ISI][Medline].
266.
Sudhir, K,
Chou TM,
Chatterjee K,
Smith EP,
Williams TC,
Kane JP,
Malloy MJ,
Korach KS,
and
Rubanyi GM.
Premature coronary artery disease associated with a disruptive mutation in the estrogen receptor gene in a man.
Circulation
96:
3774-3777,
1997
267.
Sudhir, K,
Chou TM,
Messina LM,
Hutchison SJ,
Korach KS,
Chatterjee K,
and
Rubanyi GM.
Endothelial dysfunction in a man with disruptive mutation in oestrogen-receptor gene.
Lancet
349:
1146-1147,
1997[ISI][Medline].
268.
Sulistiyani St. Clair, RW.
Effect of 17-estradiol on metabolism of acetylated low-density lipoprotein by THP-1 macrophages in culture.
Arterioscler Thromb Vasc Biol
17:
1691-1700,
1997
269.
Sullivan, JM,
Vander Z,
Hughes JP,
Maddock V,
Kroetz FW,
Ramanathan KB,
and
Mirvis DM.
Estrogen replacement and coronary artery disease.
Arch Intern Med
150:
2557-2562,
1990[Abstract].
270.
Sullivan, TR, Jr,
Karas RH,
Aronovitz M,
Faller GT,
Ziar JP,
Smith JJ,
O'Donnell TF, Jr,
and
Mendelsohn ME.
Estrogen inhibits the response-to-injury in a mouse carotid artery model.
J Clin Invest
96:
2482-2488,
1995[ISI][Medline].
271.
Suzuki, A,
Mizuno K,
Asada Y,
Ino Y,
Kuwayama T,
Okada M,
Mizutani S,
and
Tomoda Y.
Effects of 17-estradiol and progesterone on the adhesion of human monocytic THP-1 cells to human female endothelial cells exposed to minimally oxidized LDL.
Gynecol Obstet Invest
44:
47-52,
1997[ISI][Medline].
272.
Suzuma, I,
Mandai M,
Takagi H,
Suzuma K,
Otani A,
Oh H,
Kobayashi K,
and
Honda Y.
17-Estradiol increases VEGF receptor-2 and promotes DANN synthesis in retinal microvascular endothelial cells.
Invest Opthalmol Vis Sci
40:
2122-2129,
1999
273.
Takahashi, T,
Ueno H,
and
Shibuya M.
VEGF activates protein kinase C-dependent, but Ras-independent Raf-MEK-MAP kinase pathway for DANN synthesis in primary endothelial cells.
Oncogene
18:
2221-2230,
1999[ISI][Medline].
274.
Tang, JJ,
Srivastava RA,
Krul ES,
Baumann D,
Pfleger BA,
Kitchens RT,
and
Schonfeld G.
In vivo regulation of apolipoprotein A-1 gene expression by estradiol and testosterone occurs by different mechansims in inbred strains of mice.
J Lipid Res
32:
1571-1585,
1991[Abstract].
275.
The Writing Group For the Estradiol Clotting Factors Study.
Effects on haemostasis of hormone replacement therapy with transdermal estradiol and oral sequential medroxyprogesterone acetate: a one-year, double-blind, placebo-controlled study.
Thromb Haemost
75:
476-480,
1996[ISI][Medline].
276.
The Writing Group From the PEPI Trial.
Effects of estrogen or estrogen progestin regimens on heart disease risk factors in postmenopausal women.
JAMA
273:
199-208,
1995[Abstract].
277.
Tremblay, GB,
Tremblay A,
Copeland NG,
Gilbert DJ,
Jinkens NA,
Labrie F,
and
Giguere V.
Cloning, chromosomal localization, and functional analysis of the murine estrogen receptor .
Mol Endocrinol
11:
353-365,
1997
278.
Tsai, JC,
Perella MA,
Yoshizumi M,
Hsieh CM,
Haber E,
Schlegel R,
and
Ree ME.
Promotion of vascular smooth muscle cell growth by homocysteine: a link to atherosclerosis.
Proc Natl Acad Sci USA
91:
6369-6373,
1994[Abstract].
279.
Tsukamoto, A,
Kaneko Y,
Yoshida T,
Han K,
Ichinose M,
and
Kimura S.
2-Methoxyestradiol, an endogenous metabolite of estrogen, enhances apoptosis and beta-galactosidase expression in vascular endothelial cells.
Biochem Biophys Res Commun
248:
9-12,
1998[ISI][Medline].
280.
Valverde, MA,
Rojas P,
Amigo J,
Cosmelli D,
Orio P,
Bahamonde MI,
Mann GE,
Vergara C,
and
Latorre R.
Acute activation of Maxi-K channels (hSlo) by estradiol binding to the beta subunit.
Science
285:
1929-1931,
1999
281.
Van Bezooijen, RL,
Vander Bent C,
Papapoulos SE,
and
Lowik CW.
Oestrogenic compounds modulate cytokine-induced nitric-oxide production in mouse osteoblast like cells.
J Pharm Pharmacol
51:
1409-1414,
1999[ISI][Medline].
282.
Van der Burg, B,
De Groot RP,
Isbrucker L,
Kruijer W,
and
de Laat SW.
Stimulation of TPA-responsive element activity by a cooperative action of insulin and estrogen in human breast cancer cells.
Mol Endocrinol
11:
1720-1726,
1990.
283.
Van der Mooren, MJ,
Demacker PN,
Blom HJ,
de Rijke YB,
and
Rolland R.
The effect of sequential three-monthly hormone replacement therapy on several cardiovascular risk estimators in postmenopausal women.
Fertil Steril
67:
67-73,
1997[ISI][Medline].
284.
Vigano, G,
Gaspari F,
Locatelli M,
Pusineri F,
Bonati M,
and
Remuzzi G.
Dose effect and pharmacokinetics of estrogens given to correct bleeding time in uremia.
Kidney Int
34:
853-858,
1988[ISI][Medline].
285.
Wagner, JD,
Schwenke DC,
Zhang L,
Applebaum-Bowden D,
Bagdade JD,
and
Adams MR.
Effects of short term hormone replacement therapies on low density lipoprotein metabolism in cynomolgus monkeys.
Arterioscler Thromb Vasc Biol
17:
1128-1134,
1997
286.
Wagner, JD,
Zhang L,
Williams JK,
Register TC,
Ackerman DM,
Wiita B,
Clarkson TB,
and
Adams MR.
Esterified estrogens with and without methyltestosterone decrease arterial LDL metabolism in cynomolgus monkeys.
Arterioscler Thromb Vasc Biol
16:
1473-1480,
1996
287.
Wall, RT,
Harlan JM,
Harkar LA,
and
Striker GE.
Homocysteine-induced endothelial cell injury in vitro: a model for the study of vascular injury.
Thromb Res
18:
1113-1121,
1980.
288.
Walsh, BA,
Busch BL,
Mullick AE,
Reiser KM,
and
Rutledge JC.
17-estradiol reduces glycooxidative damage in the artery wall.
Arterioscler Thromb Vasc Biol
19:
840-846,
1999
289.
Walsh, BW,
Li H,
and
Sacks FM.
Effects of postmenopausal hormone replacement with oral and transdermal estrogen on high density lipoprotein metabolism.
J Lipid Res
35:
2083-2093,
1994[Abstract].
290.
Waltenberger, J.
Modulation of growth factor action. Implications for the treatment of cardiovascular diseases.
Circulation
96:
4083-4094,
1997
291.
Wang, MY,
and
Liehr JG.
Induction by estrogens of lipid peroxidation and lipid peroxide-derived malnoaldehyde-DNA adducts in male syrian hamsters: role of lipid peroxidation in estrogen-induced kidney carcinogenesis.
Carcinogenesis
16:
1941-1945,
1995[Abstract].
292.
Wang, TT,
Sathyamoorthy N,
and
Phang JM.
Molecular effects of genistein on estrogen receptor mediated pathways.
Carcinogenesis
17:
271-275,
1996[Abstract].
293.
Weatherford, DA,
Sackman JE,
Reddick TT,
Freeman MB,
Stevens SL,
and
Goldman MH.
Vascular endothelial growth factor and heparin in a biologic glue promotes human aortic endothelial cell proliferation with aortic smooth muscle cell inhibition.
Surgery
120:
433-439,
1996[ISI][Medline].
294.
Weiner, CP,
Lizasoain I,
Baylis SA,
Knowles RG,
Charles IG,
and
Moncada S.
Induction of calcium-dependent nitric oxide synthases by sex hormones.
Proc Natl Acad Sci USA
91:
5212-5216,
1994[Abstract].
295.
Wellman, GC,
Bonev AD,
Nelson MT,
and
Brayden JE.
Gender differences in coronary artery diameter involve estrogen, nitric oxide, and Ca2+ dependent K+ channels.
Circ Res
79:
1024-1030,
1996
296.
Wenger, NK,
Speroff L,
and
Packard B.
Cardiovascular health and disease in women.
N Engl J Med
329:
247-256,
1993
297.
White, RE,
Darkow DJ,
and
Lang JLF
Estrogen relaxes coronary arteries by opening BKCa channels through a cGMP-dependent mechanism.
Circ Res
77:
936-942,
1995
298.
Williams, JK,
Adams MR,
Herrington DM,
and
Clarkson TB.
Short term administration of estrogen and vascular responses of atherosclerotic coronary arteries.
J Am Coll Cardiol
20:
452-457,
1992[ISI][Medline].
299.
Williams, JK,
Honoré EK,
and
Adams MR.
Contrasting effects of conjugated estrogens and tamoxifen on dilator responses of atherosclerotic epicardial coronary arteries in nonhuman primates.
Circulation
96:
1970-1975,
1997
300.
Wingrove, CS,
Garr E,
Godsland IF,
and
Stevenson JC.
17-Oestradiol enhances release of matrix metalloproteinase-2 from human vascular smooth muscle cells.
Biochem Biophys Acta
1406:
169-174,
1998[ISI][Medline].
301.
Winkler, M,
Kemp B,
Hauptmann S,
and
Rath W.
Parturition: steroids, prostaglandin E2, and expression of adhesion molecules by endothelial cells.
Obstet Gynecol
89:
398-402,
1997
302.
Wolfe, BM,
and
Huff MW.
Effects of combined estrogen and progestin administration on plasma lipoprotein metabolism in postmenopausal women.
J Clin Invest
83:
40-45,
1989[ISI][Medline].
302a.
Xiao, S,
Gillespie DG,
Baylis C,
Jackson EK,
and
Dubey RK.
Estradiol and its metabolites differentially induce NO synthesis by human glomerular endothelial cells and inhibit glomerular mesangial cell growth (Abstract).
Hypertension
36:
710,
2000[ISI].
303.
Yamamoto, T,
Noble NA,
Cohen AH,
Nast CC,
Hishida A,
Gold LI,
and
Border WA.
Expression of transforming growth factor isoforms in human glomerular disease.
Kidney Int
49:
461-469,
1996[ISI][Medline].
304.
Ylikorkala, O,
Orpana A,
Puolakka J,
Pyorala T,
and
Viinikka L.
Postmenopausal hormonal replacement decreases plasma levels of endothelin-1.
J Clin Endocrinol Metab
80:
3384-3387,
1995[Abstract].
305.
Zancan, V,
Santagati S,
Bolego C,
Vegeto E,
Maggi A,
and
Puglisi L.
17-Estradiol decreases nitric oxide synthase II synthesis in vascular smooth muscle cells.
Endocrinology
140:
2004-4009,
1999
306.
Zayed, I,
van Esch E,
and
McConnell RF.
Systemic and histopathologic changes in Beagle dogs after chronic daily oral administration of synthetic (ethinyl estradiol) or natural (estradiol) estrogens, with special reference to the kidney and thyroid.
Toxicol Pathol
26:
730-741,
1998[ISI][Medline].
307.
Zhu, BT,
and
Conney AH.
Is 2-methoxyestradiol an endogenous estrogen metabolite that inhibits mammary carcinogenesis?
Cancer Res
58:
2269-2277,
1998[Abstract].
308.
Zoja, C,
Noris M,
Corna D,
Vigano G,
Perico N,
deGaetano G,
and
Remuzzi G.
L-Arginine, the precursor of nitric oxide abolished the effects of estrogens on bleeding time in experimental uremia.
Lab Invest
65:
479-483,
1991[ISI][Medline].