Departments of 1 Pediatrics, 2 Pathology, and 3 Physiology and Biophysics, State University of New York at Buffalo, Buffalo, New York 14214; and 4 Department of Pediatrics, Northwestern University, Chicago, Illinois 60614
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ABSTRACT |
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C-type natriuretic peptide (CNP) is a recently described
endothelium-derived relaxing factor. CNP relaxes vascular smooth muscle
and inhibits smooth muscle proliferation by binding to natriuretic
peptide receptor (NPR) type B (NPR-B) and producing cGMP. Lung
parenchyma and fifth-generation pulmonary arteries (PA) and veins (PV)
were isolated from late-gestation fetal lambs. All three types of NPR
mRNA were detected in PA and PV by RT-PCR. CNP and NPR-B immunostaining
was positive in pulmonary vascular endothelium and medial smooth
muscle. CNP concentration-response curves of PA and PV were compared
with those of atrial natriuretic peptide (ANP) by use of standard
tissue bath techniques. CNP relaxed PV significantly better than PA.
ANP relaxed PA and PV equally, but ANP relaxed PA significantly better
than CNP. Pretreating PA and PV with natriuretic peptide receptor
blocker (HS-142-1) or cGMP-dependent protein kinase inhibitor
Rp--phenyl-1- N2-etheno-8-bromoguanosine
3',5'-cyclic monophosphorothionate significantly inhibited the
CNP relaxation response, indicating that the response was
mediated through the NPR-cGMP pathway. We conclude that CNP is
important in mediating pulmonary venous tone in the fetus.
natriuretic peptide receptors; protein kinase G; guanosine 3',5'-cyclic monophosphate
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INTRODUCTION |
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AT BIRTH, SUCCESSFUL TRANSITION from gas exchange by the placenta to gas exchange by the lung depends on a dramatic decrease in pulmonary vascular resistance and an 8- to 10-fold increase in pulmonary blood flow. cGMP is an important second messenger in many biological systems including vascular smooth muscle, where it mediates relaxation. Vasoactive substances such as nitric oxide (NO), produced by the endothelium, modulate pulmonary vascular tone through production of cGMP and thus contribute to the normal fall in pulmonary vascular resistance at birth (1, 7, 8). Guanylate cyclases catalyze the production of cGMP from GTP, leading to the phosphorylation of cGMP-dependent protein kinases (PKG), calcium sequestration, and vascular smooth muscle relaxation (23).
NO is not the only potential agonist for stimulation of cGMP production in the fetal pulmonary vasculature. Natriuretic peptides also have vascular effects mediated by stimulating the production of cGMP. Atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP) are produced by cardiac tissue and have potent natriuretic and vasorelaxant properties (19). C-type natriuretic peptide (CNP) was initially identified in the central nervous system (31) and was later shown to be synthesized and released by the endothelial cells (32).
Unlike NO, which stimulates soluble guanylate cyclase (sGC), natriuretic peptides including CNP act by stimulating a membrane-bound particulate guanylate cyclase (pGC) through natriuretic peptide receptors (NPR). There are three known types of NPR. NPR-A and NPR-B are coupled to pGC enzyme activity. ANP and BNP act predominantly through the NPR-A (9), whereas CNP is a specific agonist of the NPR-B (21). Type C receptors (NPR-C) are unique in that they do not possess a kinase (pGC) moiety (33). They mediate endocytosis and subsequent degradation of all the natriuretic peptides and are considered to be clearance receptors (20).
It has been suggested that CNP acts as an endothelium-derived relaxing factor (18) in the control of vascular tone and vascular remodeling (16). Similar to NO, CNP produced in the endothelium stimulates the production of cGMP in adjacent vascular smooth muscle (5). This similarity, and the known importance of the endothelium in the pulmonary vascular changes during gestation and at birth, led us to test the hypothesis that CNP and the NPR-B are expressed in fetal lung and produce dilation of the fetal pulmonary vasculature. We have previously reported that NO is a more potent dilator of pulmonary veins (PV) than of pulmonary arteries (PA) in fetal and newborn lambs (29, 30). Therefore, we further hypothesized that, like NO, CNP would relax PV more than PA.
We used immunohistochemical techniques to localize CNP and NPR-B in lungs from late-gestation ovine fetuses. Isolated pulmonary arterial and venous segments were evaluated for mRNA expression of all three types of NPR by use of RT-PCR techniques. We further studied the effects of CNP on isolated PA and PV and compared them with the effects of ANP. Finally, the mechanism of the vascular effects of CNP was studied using inhibitors of NPR and cGMP-dependent protein kinase.
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METHODS |
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This study was approved by the State University of New York at Buffalo Laboratory Animal Care Committee. Near-term-gestation pregnant ewes (135-136 days, term being 146-150 days) were anesthetized with thiopental and halothane, and the fetuses were delivered by cesarean section. The fetus was killed before first breath by rapid exsanguination through a cardiac puncture under anesthesia. The heart and lungs were removed en bloc from the thorax.
RT-PCR to detect NPR
mRNA.
After removal of the lungs from the lamb, segments of fourth- and
fifth-generation PA and PV were dissected (n = 5 lambs). The vessel segments were frozen immediately (5 min of death) in liquid nitrogen and stored at
70°C until processed. Total cellular RNA was isolated from these tissues using TRIzol reagent (Life
Technologies, Grand Island, NY) according to manufacturer's protocol.
Samples were quantified and run on agarose formaldehyde gels to confirm
the integrity of RNA. One microgram of sample was subjected to RT-PCR
in a single tube in 50 µl of 1× PCR buffer (1.5 mM magnesium
chloride, 20 mM Tris · HCl, pH 8.4, and 50 mM KCl) containing
10 mM dATP, dGTP, dCTP, and dTTP, 30 pM forward and reverse
primers, 18S internal standards (Ambion, Austin TX), 2.5 U of AMV
reverse transcriptase, and 2.5 U of Taq polymerase (both
from Roche Molecular Biochemicals, Indianapolis, IN). Each reaction was
subjected to denaturation/annealing at 65° for 10 min, reverse
transcription at 50°C for 10 min, and denaturation and inactivation
of reverse transcriptase at 94°C for 4 min, followed by 25 cycles at
94°C for 1 min, 60°C for 2 min, and 72°C for 2 min, with a final
extension at 72°C for 10 min. Negative controls contained no
reverse transcriptase. Cycling profiles for each pair were done with 25 cycles being on the linear part of the cycle vs. product curve.
Immunohistochemistry. Right upper and lower lobes from six lambs were removed, and the vascular tree was flushed first with normal saline followed by 4% buffered formalin. A 50-ml syringe was inserted into the main stem bronchus, and lung airspaces were infused with 4% buffered formalin until the lobe was firm. The airway was then sutured closed, and the entire lobe was submerged in a formalin-filled container for 24 h. Five to six tissue blocks were cut (~2 cm3) from each of six animals. Tissue blocks were washed, dehydrated in ethanol, and embedded in paraffin. Sections were cut at 5 µm and mounted on poly-L-lysine (Sigma Chemical, St. Louis, MO)-coated slides.
The primary antibodies utilized were as follows: rabbit anti-CNP (human, porcine, rat) (22, 53), which has been shown by the manufacturer not to cross-react with either ANP or BNP, was purchased from Peninsula Laboratories (Belmont, CA); rabbit anti-NPR-B (Z657) was obtained as a gift from Dr. David Garbers (University of Texas Southwestern Medical Center). The anti-NPR-B antibody is directed against the carboxy terminus of the peptide and does not cross-react with NPR-A. For negative controls, sections were incubated with normal rabbit serum in place of the primary antibody. Sections were deparaffinized in three changes of xylene, hydrated in a graded ethanol series, and washed in tap water. Endogenous peroxidase activity was blocked by immersing slides in 0.3% H2O2 for 30 min. After being washed in PBS, slides were incubated for 1 h with 6% horse serum to block nonspecific binding of the primary antibody. The blocking serum was removed by gentle tapping, and slides were incubated overnight at room temperature in a humidified container with either anti-CNP (1:600) or anti-NPR-B (1:3,000). Detection of primary antibody binding was accomplished using the Vectastain Elite horse anti-rabbit Avidin Biotin Complex kit (Vector Laboratories, Burlingame, CA). The following day, slides were washed thoroughly in PBS, and the biotinylated secondary antibody was applied for 45 min. After being washed in PBS, the peroxidase-labeled complex reagent was added, and the slides were incubated for 30 min. Antibody binding was visualized using 3,3'-diaminobenzidine tetrahydrochloride and H2O2 and Sigma Fast DAB (Sigma). Slides were washed in running tap water, counterstained lightly with Mayer's hematoxylin, and mounted in Permount (Fisher Scientific, Fair Lawn, NJ).Isolated vessel study. Fifth-generation PA and PV were dissected, isolated, and cut into rings (n = 20 lambs) as described previously (29). Rings were suspended in water-jacketed chambers filled with aerated (94% O2-6% CO2) modified Krebs-Ringer solution (in mM: 118 NaCl, 4.7 KCl, 2.5 CaCl2, 1.2 MgSO4, 1.2 KH2PO4, 25.5 NaHCO3, and 5.6 glucose) at 37°C. A continuous recording of isometric force generation was obtained by tying each vessel ring to a force-displacement transducer (model UC2, Statham Instruments, Hato Rey, PR) that was connected to a recorder (Gould Instrument Systems, Valley View, OH). After the vessel rings were mounted, they were allowed to equilibrate for 20 min in the bathing solution. A micrometer was used to stretch the tissues repeatedly in small increments over the following 45 min until resting tone remained stable at a passive tension of 0.8 g for arteries and 0.6 g for veins. Preliminary experiments determined that this procedure provided optimal length for generation of active tone to exogenous norepinephrine (NE). The maximal contractile tension of each ring was determined by exposure to KCl (118 mM). Wet tissue weights were obtained at the end of each experiment, and responses were normalized by tissue weight.
The following pharmacological agents were used: indomethacin, DL-propranolol, N-nitro-L-arginine (L-NNA), L-norepinephrine hydrochloride, ANP (rat ANP 1-28), and CNP (human CNP 22; Peptides International, Louisville, KY). All other drugs were purchased from Sigma-Aldrich. The NPR antagonist, HS-142-1, was a gift from Dr. S. Nakanishi (Kyowa Hakko, Tokyo Research Laboratories, Tokyo, Japan). This compound selectively blocks NPR-A and -B but not the C receptor (25). In the canine coronary circulation, this agent specifically attenuates CNP-mediated vasodilation and does not alter vasodilation induced by acetylcholine (36). The specific PKG inhibitor, Rp- ![]() |
RESULTS |
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RT-PCR.
RT-PCR analysis for detection of NPR-A, -B, and -C in isolated
fifth-generation PA and PV yielded single, distinct, appropriately sized bands for each cDNA. Subsequent sequencing of the products and
comparison with published sequences for NPR-A (22), -B
(6), and -C (12) determined that each primer
pair yielded the expected product. A representative sample is shown in
Fig. 1. NPR-B mRNA content (normalized to
the 18S signal) tended to be higher in PV than in PA (signal/18S ratio
1.81 ± 0.34 in PV vs. 0.92 ± 0.28 in PA, P = 0.07). In contrast, NPR-A mRNA content was similar in PV and PA
(signal/18S ratio 1.41 ± 0.16 in PV vs. 1.31 ± 0.31 in PA).
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Immunohistochemistry.
Staining was absent within all structures in all sections incubated
with normal rabbit serum in place of primary antibody (Fig.
2). The intensity and pattern of staining
for both CNP and NPR-B were consistent for all six animals examined.
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Isolated vessel studies. The constrictor response to NE (expressed as grams of tension per gram of tissue weight) was 495.7 ± 39.3 g/g in PV and 252.1 ± 25 g/g in PA. However, the level of constriction was similar between the two vessel types when compared as a percentage of their maximal constriction to 118 M KCl (63 ± 8% in veins vs. 72 ± 4% in arteries, P = nonsignificant).
Relaxation responses to increasing concentrations of CNP (10
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DISCUSSION |
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We studied the CNP-pGC system in pulmonary arteries and veins isolated from normal, late-gestation fetal lambs. Using RT-PCR, we demonstrated the presence of all of the three NPR mRNAs (NPR-A, -B and -C) in pulmonary arteries and veins (Fig. 1). Having detected NPR mRNA in pulmonary arteries and veins, we localized CNP and NPR-B protein within these vessels by immunohistochemistry. CNP was localized primarily to the endothelium and smooth muscle of large arteries and veins (Fig. 2, A and C). NPR-B was localized in the smooth muscle of large arteries and veins and resistance arteries.
Recently, Nakanishi et al. (26) reported the ontogeny and localization of CNP expression in the rat embryo lung. CNP mRNA was present in embryonic lung and increased rapidly during the immediate postnatal period. Similarly, CNP mRNA and immunoreactivity localized to vascular smooth muscle cells just before birth and expression increased with advancing postnatal age. Jankowski et al. (17) reported that rat pulmonary parenchymal NPR-B mRNA content is low on postnatal day 1, increased on day 4, and decreased thereafter. They did not determine localization of NPR-B expression.
Although ontogeny was not the focus of the current study, we examined NPR mRNA expression and localized CNP and NPR-B within the pulmonary vasculature of late-gestation ovine fetuses. We chose the fetal lamb because many physiological and pathological studies of the perinatal pulmonary vasculature have been performed in fetal lambs and because models of pulmonary hypertension can be relatively easily developed in this species (1, 8). It is important to note that the chronology of lung development differs from rats to sheep and humans (2). Rats have immature saccular lungs at birth, whereas lambs and humans have mature alveolar lungs at term gestation (4).
In the present study, we did not examine CNP mRNA. However, using immunohistochemical staining, we found abundant immunoreactive CNP in the endothelium of the large pulmonary arteries and veins, likely representing areas of CNP synthesis. The absence of NPR-B staining in the endothelium and its presence in the smooth muscle indicate that smooth muscle is the likely primary site of action of CNP. The distribution of CNP protein in smooth muscle cells parallels the distribution of NPR-B. This CNP immunoreactivity in the smooth muscle could be secondary to its binding to the NPR-B or may represent active CNP synthesis in the smooth muscle (26).
In the current study, we observed that CNP and NPR-B immunoreactivity in pulmonary arterial smooth muscle was more intense toward the adventitial layer (Fig. 2, A and B), whereas their distribution was more uniform throughout the medial layer in pulmonary veins. The significance of this differential pattern of distribution of CNP and NPR-B protein within the medial layer of large arteries is not clear.
Functional responses to exogenous CNP were studied in isolated pulmonary arteries and veins. These effects were compared with the known effects of ANP (30) on fetal pulmonary vessels. CNP and ANP were used for comparison because of their respective specificity for NPR-B and -A, respectively (14, 21). Although both peptides relaxed each type of vessel tested, distinct differences were observed. CNP was a significantly more potent vasodilator in pulmonary veins than in arteries. This pattern is similar to what we have previously reported for NO (29, 30). In contrast, ANP produced equivalent relaxation in arteries and veins. A differential distribution of NPR-A receptors to pulmonary arteries and NPR-B to pulmonary veins is the most likely explanation for these findings. This pattern of arterial and venous responses to ANP and CNP is similar to that reported in systemic vessels isolated from dogs (35) and humans (37). Perreault et al. (27) have reported that pulmonary veins from neonatal piglets have fewer NPR-A than pulmonary arteries.
The constrictor response to NE was greater in pulmonary veins than arteries, perhaps in part due to pretreatment with L-NNA, which we previously reported to constrict pulmonary veins more than arteries in lambs (29). Although it is possible that these differences in constrictor response contributed to the enhanced venous relaxations to CNP, we found relaxations to ANP were very similar in arteries and veins (Fig. 5). Furthermore, the constrictor response to NE was equivalent in veins and arteries when expressed as a percentage of maximal constriction to 118 M KCl. Therefore, we believe that venous relaxations to CNP are greater because of differences in NPR-B expression.
We used HS-142-1, which inhibits both NPR-A and NPR-B (25, 28), to determine whether CNP relaxed pulmonary vessels through receptor-mediated activation of pGC. HS-142-1 has been shown to inhibit CNP-mediated relaxation of canine coronary arteries (36) and ANP-mediated relaxation of rabbit thoracic aorta. We were able to conduct experiments with HS-142-1 in only a limited number of animals because it is no longer manufactured (Dr. S. Nakanishi, personal communication), but we found a significant inhibition of CNP-mediated relaxation in both pulmonary arteries and veins. The degree of inhibition observed in the current study is similar to that previously reported with ANP-mediated relaxation of isolated rabbit thoracic aorta (15).
We used Rp-8-Br-PET-cGMPS, a potent inhibitor of cGMP-dependent PKG, to determine whether CNP relaxations were mediated by cGMP and activation of PKG. Rp-8-Br-PET-cGMPS has been reported to inhibit relaxations to NO donors (3) and 8-Br-cGMP (13). Significant attenuation of CNP-mediated relaxation by Rp-8-Br-PET-cGMPS pretreatment in both pulmonary arteries and veins demonstrates that CNP relaxes these vessels, at least in part, by a cGMP-PKG-dependent mechanism. To our knowledge, this is the first reported use of this compound to inhibit NPR-mediated relaxation.
In conclusion, we found that CNP and its receptors are present in the pulmonary circulation of late-gestation fetal lambs. We also found that exogenous CNP relaxes pulmonary veins and arteries and that this relaxation is mediated by the NPR-pGC-cGMP-PKG pathway. Similar to NO, CNP is a more potent dilator of pulmonary veins than of pulmonary arteries. We speculate that CNP may act in a paracrine fashion to modulate vasomotor tone and smooth muscle cell proliferation in pulmonary vessels. Further experiments will be necessary to elucidate the exact role of CNP in physiological transition at birth and in pathological states associated with pulmonary hypertension.
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ACKNOWLEDGEMENTS |
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We gratefully acknowledge Daniel D. Swartz and Huamei Wang for expert technical assistance in performing these experiments.
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FOOTNOTES |
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This work was supported by National Heart, Lung, and Blood Institute Grant HL-54705 (R. H. Steinhorn) and American Heart Association Grant 9740024 (R. H. Steinhorn).
Address for reprint requests and other correspondence: R. H. Steinhorn, Div. of Neonatology, Children's Memorial Hospital, 2300 Children's Plaza no. 45, Chicago, IL 60614 (E-mail: r-steinhorn{at}northwestern.edu).
The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
Received 20 November 2000; accepted in final form 13 March 2001.
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