Instituto de Biología y Medicina Experimental, Consejo Nacional de Investigaciones Científicas y Técnicas V, Obligado 2490, (1428) Buenos Aires, Argentina
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ABSTRACT |
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We evaluated the effects of angiotensin II (ANG
II) and its antagonists on prolactin release, intracellular calcium
([Ca2+]i)
mobilization, and
[3H]thymidine uptake
in cells from normal rat pituitaries and from estrogen-induced
pituitary tumors. ANG II
(107 to
10
9 M) increased prolactin
release significantly in control and not in tumoral cells. In control
cells, ANG II (10
6 to
10
9 M) produced an
immediate spike of
[Ca2+]i
followed by a plateau. Spike levels rose significantly between 10
10 and
10
8 M ANG II, whereas the
onset of the spike was retarded with decreasing concentrations. In
tumoral cells, ANG II did not produce a spike phase even at
10
6 M. ANG II-induced
prolactin release and calcium mobilization were blocked by losartan
(AT1 receptor antagonist) and not
by PD-123319 (AT2 antagonist).
Finally, [3H]thymidine
uptake was not modified by ANG II
(10
7 to
10
10 M) or its antagonists
in either group. Our results suggest that chronic in vivo estrogenic
treatment alters in vitro pituitary response to ANG II. Alterations
might function to limit excessive prolactin secretion of hypersecreting
tumors. Besides, ANG II does not modify DNA synthesis in vitro of cells
from normal or tumor-derived hypophyses.
calcium; estrogen
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INTRODUCTION |
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IT HAS BEEN DESCRIBED that all the components of the renin-angiotensin system (RAS) are present in the pituitary and that angiotensin II (ANG II) is produced locally (7). ANG II releases prolactin (PRL) both in vivo and in vitro (8), and specific ANG II receptors, belonging to the AT1 subtype, have been identified mainly in lactotrophs (18). In the anterior pituitary AT1 receptor, stimulation is coupled to phospholipase C-mediated hydrolysis of membrane phosphoinosites, leading to the formation of diacylglycerol and inositol phosphates and subsequently to the activation of protein kinase C (PKC) and to an increase in intracellular calcium ([Ca2+]i) levels (4, 21).
On the other hand, ANG II has been proposed to act as a growth factor in several tissues on the basis of its ability to stimulate protein synthesis and cell growth (29, 31). In fact, increases in both PKC and [Ca2+]i induced by ANG II have been shown to promote the expression of the growth-related immediate early genes such as c-fos, c-jun, and c-myc in smooth muscle cells (24). The role of ANG II on growth is complex, and the peptide has been postulated to modulate growth in concert with other promoters (17, 31). This feature would be of great importance in the regulation of the proliferation of malignant cells and in the progression of tumor growth, keeping in mind the potential ability of ANG II to accelerate angiogenesis (16). Although both subtypes of ANG II receptors (AT1 and AT2) have been shown to be expressed in tumoral and in developing tissues, there is increasing evidence that shows that distinct growth-modulating actions (proliferative or antiproliferative) of the octapeptide are coupled to different receptor subtypes (29).
Chronic administration of estrogens to rats induces enlargement of the anterior pituitary and increased synthesis and secretion of PRL. Histologically, tumors are composed of hyperplastic and hypertrophied lactotrophs, with involution of somatotrophs and gonadotropin-producing cells (6). Damage to hypothalamic dopaminergic neurons in response to estrogen has been described (26), and a direct action of estrogen at the pituitary level has also been suggested. For example, a high rate of DNA polymerase activity (19) and a description of an estrogen-responsive element in the 5'-flanking region of the PRL gene in the tumors (9) are consistent with direct stimulation of lactotroph proliferation by estrogens. In addition, estrogen-induced hyperplasia of the anterior pituitary is associated with the development of a direct arterial blood supply (10), and the mechanism of arterial growth might be analogous to the process of angiogenesis observed coincident with tumor formation.
Therefore, in view of the PRL-releasing action of ANG II and of its participation in cellular proliferation and in angiogenesis in several tissues, we attempted to elucidate if the octapeptide was involved in the regulation of prolactinomas induced by estradiol in rats. In this context we examined comparatively in dispersed adenohypophyseal cells from normal pituitaries and from estrogen-induced prolactinomas (tumors) the effects of ANG II and of antagonists of ANG II receptor subtypes on 1) PRL release as a measure of the secretory capacity of the adenohypophysis, 2) [Ca2+]i mobilization as this cation has been shown to participate both in hormonal secretion and in the trophic actions of ANG II, and 3) [3H]thymidine uptake to evaluate DNA synthesis.
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MATERIALS AND METHODS |
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Animals.
Female 60-day-old Sprague-Dawley rats were housed in an air-conditioned
room with lights on at 0700 and off at 1900. They had free access to
laboratory chow and tap water. Pituitary tumors were induced by
subcutaneous administration of estradiol-valerate (0.5 mg · kg body
wt1 · wk
1)
for 6-7 wk. Rats in diestrus were used as controls. Pituitary weights at euthanasia were 7.8 ± 2.3 and 32.5 ± 7.2 mg for control and tumor group, respectively.
Drugs. ANG II was from Sigma (St. Louis, MO), losartan (DUP-753) was a gift from DuPont Merck (Wilmington, DE), and PD-123319-121b was a gift from Parke-Davis (Ann Arbor, MI). PD-123319 is similar to AT2 ligands PD-123177 and PD-121981 (27). Epidermal growth factor (EGF) was from Sigma.
Cell dispersion. Rats were killed by decapitation at 0900, and normal or tumoral pituitaries were removed on ice, separated from the neurointermediate lobe, and placed in chambers containing freshly prepared Krebs-Ringer bicarbonate buffer (KRBGA) without Ca2+ or Mg2+. Buffer containing 14 mM glucose, 1% bovine serum albumin (BSA, Sigma), 2% Eagle's minimum essential medium (MEM) amino acids (GIBCO, Buenos Aires, Argentina), and 0.025% phenol red was previously gassed for 15 min with 95% O2 and 5% CO2 and adjusted to pH 7.35-7.40. Buffer was filtered through a membrane (Nalgene) with a pore diameter of 0.22 µm. Hypophyses were washed three times with KRBGA and then cut in 1-mm pieces. Obtained fragments were washed and incubated in the same buffer containing 0.2% trypsin for 30 min at 37°C, 95% O2, and 5% CO2. They were then treated for two additional minutes with deoxyribonuclease I (Sigma, 1 mg/ml), and digestion was ended by adding 0.2% of newborn calf serum (GIBCO). Fragments were dispersed in individual cells by gentle trituration through siliconized Pasteur pipettes. Resulting suspension was filtered through a nylon gauze (160 µm) and centrifuged 10 min at 1,200 g. Before centrifugation, an aliquot of cellular suspension was taken to quantify hypophyseal cell yield, using a Neubauer chamber. Viability of cells determined by trypan blue was always >95%.
Cell cultures.
The cell pellet from tumoral or control rats was resuspended in a
Dulbecco's modified Eagle's medium (DMEM), supplemented with 10%
horse serum, 2.5% fetal calf serum, 1% MEM nonessential amino acids,
25,000 U/l of micostatin and 25 ng/l gentamicin. Cells were plated in
sterile tissue culture plates (Corning, Cluster 96; 60,000 cells/well)
and incubated with 300 µl DMEM (GIBCO) in a metabolic incubator at
37°C with 5% CO2 and 95%
O2. After long-term incubation (96 h), cells were washed twice with DMEM [with addition of F-12
nutrient mixture (GIBCO), 2.2 g/l
CO3HNa, and 0.1% BSA] to
remove all traces of serum. Experimental incubations were performed in
300 µl DMEM alone (controls) or with different combinations of the
pharmacological agents (ANG II 1 × 106 to 1 × 10
10 M, losartan 1 × 10
6 M, PD-123319 1 × 10
6 M, in quadruplicate).
For analysis of PRL secretion, samples were taken at 30 min of
incubation period. They were subsequently stored at
20°C
until analyzed by radioimmunoassay after appropriate dilution with 0.01 M phosphate-buffered saline with 1% egg albumin. Experiments were
repeated five times. Time and concentrations were chosen according to
our previous experience
(3)
Radioimmunoassays. PRL was measured by radioimmunoassay using kits provided by the National Institute of Diabetes and Digestive and Kidney Diseases. Results are expressed in terms of PRL reference preparation. Intra- and interassay coefficients of variation were 7.2 and 12.8%, respectively.
[Ca2+]i
measurements.
Fura 2-acetoxymethyl ester (fura 2-AM, Sigma) was used as a fluorescent
indicator. In preliminary experiments, studies on calcium mobilization
were carried out in cells that had been cultured in identical
conditions as those in experiments of secretion and [3H]thymidine
incorporation. Because no differences in calcium response both in
control and tumoral cells were observed using freshly isolated cells,
this last methodology was chosen. The pellet of adenohypophyseal cells
of each experimental group was redispersed and incubated in a buffered
saline solution [BSS (in mM): 127 NaCl, 5 KCl, 0.5 KH2PO4,
5 NaHCO3, 1.8 CaCl2, 2 MgCl2, and 10 N-2-hydroxyethylpiperazine-N'-2-ethanesulfonic
acid; pH 7.5] in the presence of 1.5 µM fura 2-AM, 10 mM
glucose, and 0.1% BSA. Cells were incubated for 30 min at 37°C in
an atmosphere of 5% CO2, the time
during which fura 2-AM was incorporated into the cells and converted by
endogenous esterases to the fluorescent indicator fura 2 in the
cellular cytoplasm. Cells were then washed twice in BSS without fura
2-AM and prepared at a density of 1.7-2 × 106 cells/ml. Fluorescence was
measured in a spectrofluorometer (Jasco, Tokyo, Japan) provided with
the accessory CA-261 to measure
Ca2+ with continuous stirring,
thermostat adjusted to 37°C, and injection chamber.
[Ca2+]i
levels were registered every second by exposure to alternating 340- and
380-nm light beams, and the intensity of light emission at 505 nm was
measured. In this way, light intensities and their ratio (F340/F380)
were followed. Drugs (5 µl) were injected into the chamber as a
100-fold concentrated solution. ANG II (concentration in chamber
105 to
10
10 M) was administered at
minute
2. When the effect of ANG II
antagonists was tested, losartan
(AT1 specific) or PD-123319
(AT2 specific) was added (final
concentration: 10
7 M) 1 min
before the ANG II stimulus (final concentration:
10
9 M). The preparation was
calibrated, determining maximal fluorescence induced by Triton X-100
0.1% and minimal fluorescence in the presence of 5 mM ethylene
glycol-bis(
-aminoethyl
ether)-N,N,N',N'-tetraacetic acid (pH adjusted to >8.3).
[Ca2+]i
was calculated according to Grynkiewicz et al. (13). Basal values were
considered as those measured during the 1st min of the experiment.
Values were corrected for dye leakage and autofluorescence. Resulting
graphs were scanned, processed, and quantified using software Ungraph
2.0, and Excel 5.0. Results were normalized with respect to average
basal levels (between 90 and 120 s).
DNA synthesis.
Culture procedure was the same as described in Cell
cultures.
[3H]thymidine (0.2 µCi/well; DuPont NEN, 87.7 Ci/mmol) was added to cultures after
addition of stimuli (ANG II
107 to
10
10 M and EGF 20 ng/ml).
After 24 h of incubation, medium was discarded and the cells were
removed and lysed by treatment with 0.05% trypsin and 0.02% EDTA in
deionized water. Twenty minutes later the reaction was stopped by
filtering under vacuum through GF/C Whatman filters using the Nunc Cell
Harvester 8. After five washes with deionized water, the filters were
placed in plastic vials with 3 ml of scintillation solution and
radioactivity was counted in a Beckman counter. Each experiment was
repeated four times.
Statistical analyses. Hormone secretion and [3H]thymidine uptake results were analyzed by two-way analysis of variance (ANOVA) for the effects of group (control or tumor) and drug. If F of interaction was found to be significant (P < 0.05), individual means were compared by Scheffé's test; if it was not significant, groups of means were analyzed by the same test.
For calcium experiments means of peak values (maximum levels achieved in the first 40 s after application of stimulus) and latency to the peak (seconds elapsed from stimulus to peak values) were analyzed by one-way ANOVA. ![]() |
RESULTS |
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Effect of ANG II on PRL secretion. At 30 min of incubation, basal PRL release was greater in tumoral than in control cells (143.0 ± 43.3 vs. 60.6 ± 15.1 ng/well, P < 0.05).
The effect of ANG II on PRL secretion differed between groups. ANG II released PRL significantly at the concentrations 1 × 10
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Effect of ANG II on
[Ca2+]i
mobilization.
Changes in
[Ca2+]i
induced by ANG II (1 × 106 M and 1 × 10
8 to 1 × 10
10 M) were monitored in a
suspension of dispersed pituitary control or tumoral cells. We used
freshly dispersed adenohypophyseal cells, considering that ANG II
receptors are mainly located in lactotrophs and secondarily in
corticotrophs, which constitute <5% of hypophyseal cell population.
Basal
[Ca2+]i
was 180.10 ± 8.67 and 217.13 ± 18.30 nM,
respectively. The response evoked in control cells was significantly
greater and markedly different from that in tumoral cells.
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Effect of ANG II on cell DNA synthesis.
No significant effect of ANG II (at the doses of
107 to
10
10 M) or of the
antagonists (10
7 M) on cell
DNA synthesis was observed in either group (Fig. 6). Combinations of ANG II and both antagonists were equally ineffective (data not shown). EGF used as positive control increased
[3H]thymidine uptake,
and the effect was significantly greater in tumoral cells.
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DISCUSSION |
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It is well documented that ANG II releases PRL by interaction with pituitary AT1 receptor through a calcium-dependent process. The initial spike response of Ca2+ mobilization induced by ANG II is independent of Ca2+ influx to the cell and reflects Ca2+ release from the endoplasmic reticulum induced by inositol trisphosphate (IP3), whereas the plateau phase requires Ca2+ entry to the cells mainly through voltage-sensitive calcium channels (VSCC). In the present experiments we first studied in detail the concentration-related response of [Ca2+]i to ANG II in adenohypophyseal control cells and describe an increase in spike magnitude and a decrease in latency to spike with increasing concentrations of ANG II. It has been described that ANG II increased IP3 formation already at 10 s (4), in good correlation with our results in which [Ca2+]i spikes were demonstrated at 14-41 s, depending on the concentration used. Latency between arrival of the agonist and the onset of the calcium response was particularly long at low agonist concentrations and may be explained by the time required to generate sufficient IP3 to release [Ca2+]i. This phenomenon has also been described for TRH acting on lactotrophs (1).
In cells from tumor-bearing rats the pattern of response was altered. ANG II did not evoke clear spike elevations of [Ca2+]i even at high concentrations. In correlation, the sensitivity of PRL release in response to different concentrations of ANG II was lower in this group, even though ANG II produced a plateau rise in [Ca2+]i levels. These results enhance the importance of the transient spike phase of Ca2+ mobilization in relation to hormone release. PRL secretion can be achieved by increasing Ca2+ entry through VSCC, but it has been shown that only the initial burst in [Ca2+]i correlated with TRH-stimulated PRL production (25) and that, in gonadotropes, inhibition of this burst by gonadotropin-releasing hormone (GnRH) pretreatment prevented luteinizing hormone release in response to a subsequent pulse of GnRH (30). On the other hand, altered sensitivity of the associated PRL-releasing effect of ANG II was specific and did not merely reflect an incapacity of the hypersecreting cell to increase secretion even further. This was evidenced using TRH, which evoked a marked PRL release in tumoral as well as in control cells. It has been described that acute in vitro treatment with estrogen did not alter PRL response to ANG II (5). Therefore, it is probable that, in pituitaries that have been administered estrogen for 6 wk, there are marked alterations that cannot be detected after only 48 h of treatment.
Estrogens can modulate many aspects of the peripheral and pituitary RAS. They increase plasma angiotensinogen levels, enhance angiotensinogen mRNA in the liver, brain, and pituitary (15), and, what is more important, ANG II receptor number in the pituitary fluctuates during the estrous cycle, with highest binding in diestrus and lowest in estrus (27). This feature is in accordance with the finding that estrogen treatment reduces ANG II receptor number in the hypophysis, as measured by binding studies and by autoradiography (5, 18, 27). Nevertheless, changes in receptor number described range from two- to ninefold, and the decrease in sensitivity of ANG II-induced PRL release and Ca2+ mobilization is greater. Therefore, we cannot conclude that differences found are simply due to changes in receptor number. Reduced efficiency of Ca2+ mobilization by D-myo-inositol 1,4,5-trisphosphate, as described in homologous desensitization to GnRH (22), or another mechanism could also participate. The decrease in ANG II receptors coupled to altered [Ca2+]i mobilization and hormone release, which we describe, could represent a safety mechanism to control excessive PRL secretion when the effect of the major inhibitory neurohormone, dopamine, is reduced.
On the other hand, the modification in [Ca2+]i mobilization could reflect an overall altered Ca2+ metabolism in tumoral cells. Elevation of cytosolic free calcium plays an important role in the regulation of growth, participating in gene expression and cell division. For example, ANG II evoked alterations in [Ca2+]i in human lung adenocarcinoma cell lines and not in a normal lung cell line (2). In contrast, in our cells from pituitary tumors ANG II-induced [Ca2+]i mobilization was reduced, or at least markedly altered. In several studies, tumoral or clonal cell lines are used to evaluate the effects of neurohormones on calcium metabolism (11, 23). The present results indicate that tumor cell lines are not always adequate models to study calcium dynamics in pituitary cells. On the other hand, alterations in calcium metabolism in tumoral cells were not associated with changes in DNA synthesis in the present experiments, as revealed by the studies of [3H]thymidine uptake, but were probably associated with alterations in hormone secretion.
It has been well documented that estrogen treatment produces not only
hyperprolactinemia, but also cell proliferation of lactotrophs and
arteriogenesis. ANG II increases protein synthesis and promotes cell
growth in a number of cells, including fibroblasts, vascular smooth
muscle cells, adrenocortical cells, and myocardial cells, by a
mechanism involving PKC activation, increase in
[Ca2+]i
levels, and induction of c-fos (12,
31). It also participates in angiogenesis (16). These findings inspired
us to investigate the effects of ANG II on DNA synthesis in control and
tumoral pituitary cells. Results indicate that in this experimental
model ANG II is not a mitogenic agent in the pituitary. In contrast, it
has been described in estrogen-induced pituitary hyperplasia that ANG
II at the concentration of
1010 M and not at higher or
lower concentrations induced pituitary cell proliferation, which was
not inhibited either by losartan or by PD-123177 (20). Differences in
the experimental model (rat strain, estrogenic dose, or time of
treatment) might account for discrepancies encountered. Besides, it has
been described that ANG II-induced hypertrophy in renal proximal
tubular cells depends on previous ANG II induction of TGF-
(31) and
that, in vascular smooth muscle cells, ANG II requires the presence of
a competence growth factor, such as platelet-derived growth factor, or
of EGF and fibroblast growth factor to exert its mitogenic effect (17).
Therefore, we cannot rule that in the hypophysis ANG II may induce
proliferation acting in conjunction with other growth factors or at
longer periods of time.
Nevertheless, from the present results the participation of ANG II in transformed adenohypophyseal cells cannot be excluded, because it has been described that certain genes are expressed only in malignant phenotype in rat pituitary tumors (28).
The growth modulatory actions (proliferative or antiproliferative) of ANG II depend on the type of ANG II receptor present on a given cell under physiological conditions (29). For example, in coronary endothelial cells the growth-promoting effects mediated by the AT1 receptor were offset by the antiproliferative actions of the AT2 receptor and could therefore be unmasked only blocking AT2 receptors with PD-123177 (29). In the anterior pituitary the receptor subtype described is the AT1 (18), but, as in certain tissues that undergo tumorigenesis, there is induction of different ANG II receptor subtypes (14). We evaluated the effect of ANG II antagonists of receptor subtypes alone and in combination with ANG II on basal DNA synthesis, PRL release, and [Ca2+]i mobilization. Neither antagonist per se had any effect on DNA synthesis, hormone release, or basal [Ca2+]i, and the positive actions of ANG II were blocked only by losartan and not by PD-123319. From these results it can be implied that in tumoral pituitaries the receptor subtype present is the AT1 as in the normal pituitary.
In conclusion, we have characterized the concentration-related response of [Ca2+]i to ANG II in control adenohypophyseal cells in correlation with PRL secretion induced by the secretagogue. We also describe that chronic in vivo treatment with estrogens alters the response of pituitary cells to ANG II in vitro. There is a decrease in [Ca2+]i mobilization induced by the octapeptide in correlation with a decreased sensitivity to the PRL-releasing effect of the same. These alterations might function to limit the magnitude of PRL secretion of the hypersecreting tumors. On the other hand, there is no modification in the subtype of receptor to ANG II (AT1) involved in such responses. Finally, ANG II does not modify in vitro DNA synthesis of cells from normal or tumor-derived hypophyses.
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ACKNOWLEDGEMENTS |
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This work was supported by Consejo Nacional de Investigaciones Científicas y Técnicas, Argentina; Fundación Antorchas and Universidad de Buenos Aires.
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FOOTNOTES |
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Address for reprint requests: C. Libertun, Instituto de Biología y Medicina Experimental, CONICET V, Obligado 2490, (1428) Buenos Aires, Argentina.
Received 10 July 1997; accepted in final form 6 November 1997.
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