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Vasodilator Actions of Urocortin and Related Peptides in the Human Perfused Placenta in Vitro¹

Discipline of Reproductive Medicine (I.M.L., A.L.A.B., C.B., W.A.W.W.), Division of Obstetrics and Gynecology (M.A.R.), and Endocrine Unit (R.S.), Mothers and Babies Research Center, University of Newcastle, John Hunter Hospital, Newcastle, New South Wales 2310, Australia

Address all correspondence and requests for reprints to: Dr. Ian M. Leitch, at present address: Miravant Pharmaceuticals Inc., 7408 Hollister Avenue, Santa Barbara, California 93117. E-mail: Ileitch{at}miravant.com

	Abstract

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Urocortin, is a recently isolated peptide belonging to the CRH family that binds with high affinity to the CRH₂ receptor. Like CRH, urocortin causes hypotension in the rat, but its vasoactive actions have not yet been studied in the human. We have compared the vasoactive properties of urocortin, CRH, and urotensin-1 in the human fetal placental vasculature in vitro. Single placental lobules were bilaterally perfused (maternal and fetal sides, 5 mL/min each; 95% O₂-5% CO₂; 37 C), and changes in fetal arterial perfusion pressure were recorded. Submaximal vasoconstriction was induced by PGF₂ (4 ± 0.7 µmol/L), which increased perfusion pressure from 19.6 ± 1.4 to 100.7 ± 3.1 mm Hg (n = 38; P < 0.001). Subsequent fetal arterial infusion of urocortin (0.001–1 nmol/L) caused concentration-dependent vasodilatation. Urocortin was equipotent with urotensin-1 and 25 times more potent than CRH in causing vasodilatation. Nevertheless, the maximum vasodilator responses to each of the peptides were similar (P > 0.05). The CRH receptor antagonist, -helical CRH-(9–41) (0.2 nmol/L) significantly attenuated the vasodilatation produced by urocortin, urotensin-1, and CRH (P < 0.05). These results indicate a possible physiological role for urocortin in the modulation of human fetal placental vascular tone by activation of CRH₂-like receptors.

	Introduction

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UROCORTIN, is a recently isolated 40-amino acid peptide belonging to the CRH family. It was first identified in rat midbrain (1), and subsequently, the human gene was localized to chromosome 2 (2). Urocortin has sequence homology with urotensin 1 (63%), which was originally identified in the caudal neurosecretory system of the teleost fish Catostomus commersoni (3), and human CRH (45%). All three peptides release ACTH from rat anterior pituitary cells (2). In addition, urocortin and urotensin-1 administered iv in conscious rats were more potent than CRH in causing hypotension (1, 4). However, the effects of urocortin in human tissue have not yet been reported.

The actions of urocortin and related peptides are mediated through two major classes of CRH receptors, designated CRH₁ and CRH₂ (5, 6, 7). These two receptors are products of separate genes, but both comprise seven putative transmembrane domains characteristic of G_s protein-coupled receptors and are positively coupled to adenylate cyclase (5, 6). The affinity of urocortin for the CRH₁ receptor is similar to those of urotensin-1 and CRH. In contrast, urocortin binds and activates the CRH₂ receptor with greater potency than CRH, suggesting that it may be the endogenous ligand for this receptor subtype (2).

CRH-binding sites have been found in human placental tissue (8, 9), and we have shown that CRH is a potent vasodilator in the fetal placental circulation (10, 11). Furthermore, the urocortin gene is expressed in the human placenta, and immunoreactive urocortin has been localized in syncytiotrophoblast cells, fetal membranes, and maternal decidua (12), raising the possibility that this peptide may have a local physiological role in placental function. We therefore investigated the vasoactive effects of urocortin in the vasculature of the human fetal placental circulation and compared them with those of piscine urotensin-1 and human CRH. In addition, we examined the possible modulation of fetal placental actions of urocortin by the CRH receptor antagonist -helical CRH-(9–41).

	Subjects and Methods

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Subjects and collection of placentas

All experiments were approved by the University of Newcastle and John Hunter Hospital human ethics committees, and women donating their placentas gave written informed consent for their use. Placentas were obtained within 20 min of vaginal delivery or cesarean section from women (aged 17–41 yr) who did not smoke and who had normotensive uncomplicated pregnancies.

Perfused placenta studies

The human perfused placental technique used in this study was described in more detail in our previous studies (11, 13). Briefly, within 20 min of delivery, the placenta was transported from the delivery suite to the laboratory and placed in a perspex bath heated to 37 C. A suitable fetal artery of the chorionic plate was cannulated with plastic tubing and connected to a Gilson Minipuls 2 peristaltic pump (Gilson Medical Electronics, Villiers-le Bel, France). A paired vein was cut at a convenient point to allow blood and perfusate to escape. The lobule was perfused with a constant flow of Krebs solution at 37 C equilibrated with 95% O₂ and 5% CO₂ containing NaCl, 97.0 mmol/L; NaHCO₃, 24.4 mmol/L; KCl, 3.0 mmol/L; KH₂PO₄, 1.2 mmol/L; CaCl₂, 1.89 mmol/L, MgSO₄, 1.0 mmol/L; and D-glucose, 5.5 mmol/L, pH 7.3, via the arterial line. The maternal side of the lobule was also perfused under the same conditions, using a plastic cannula inserted into the intervillous space through a remnant of a spiral artery in the placental basal plate. Each lobule was initially perfused at 1 mL/min for 5 min and thereafter with a constant flow rate of 5 mL/min into both the fetal and maternal circulations. Changes in the perfusion pressure (in millimeters of Hg) of the fetal placental vascular bed were recorded from the arterial perfusion line using a Gould Statham P23D transducer (Cleveland, OH) and were displayed on a Kontron 330 (Eching, Germany) flat-bed pen recorder. The effects of vasoactive agents were measured after the baseline perfusion pressure had stabilized over a period of 45–60 min.

Under the laboratory conditions used, the fetal placental lobule circulation has a low vascular resistance (14). Therefore, to detect possible vasodilator effects of urocortin, urotensin-1, or CRH, the villous vessels were constricted to 60–80% of maximum by continuous infusion of PGF₂ (0.5–20 µmol/L) into the arterial perfusing fluid using a Gilson Minipuls 3 peristaltic pump. The concentration of PGF₂ was adjusted so that a stable submaximal perfusion pressure of 90–120 mm Hg was maintained before starting a concentration-response curve to each of the three peptide agonists, and this was continued throughout the duration of the experiment. Human urocortin (0.001–1 nmol/L), piscine urotensin 1 (0.001–1 nmol/L), or human CRH (0.001–10 nmol/L) was then infused, in a gradually increasing semilog series of concentrations, into the arterial cannula perfusing the fetal vessels of the placental lobule. Infusion of each concentration of the agonists was continued for at least 20 min or until the perfusion pressure had stabilized.

In another group of experiments, the dilator effects of each of the three peptide agonists were studied in the presence of the continuous infusion of the CRH receptor antagonist -helical CRH-(9–41) (0.2 nmol/L), using a Gilson Minipuls 3 peristaltic pump. The antagonist infusion was started 30 min before the submaximal constriction with PGF₂ and was continued throughout the duration of the experiment. Vasorelaxation responses were calculated as the percent reversal of the PGF₂-induced increase in perfusion pressure before the first addition of a peptide agonist. The EC₃₀ value for each peptide was determined as the effective concentration that caused a 30% reduction in the PGF₂-induced constriction and was estimated from the concentration-response curves.

Chemicals used for the Krebs solution were of analytical grade (British Drug Houses, Kilsyth, Australia). Human urocortin (Phoenix Pharmaceuticals, Inc., Mountain View, CA) was a kind gift from Prof. E. Wei, University of California (Berkeley, CA), and was dissolved and diluted in distilled water. Human CRH and urotensin-1 (Catostomus commersoni; Peninsula Laboratories, Inc., Belmont, CA) were dissolved and diluted in distilled water as required. The CRH antagonist, -helical CRH-(9–41) (Phoenix Pharmaceuticals) was dissolved in ammonium hydroxide (Sigma Chemical Co., St. Louis, MO) at a concentration of 10 mmol/L and was diluted in distilled water as required. PGF₂ as its trometamol salt (Dinoprost, Upjohn, Australia) was supplied at a concentration of 5 mg/mL in sterile distilled water and was diluted as required in distilled water.

Statistical analyses

Statistical analyses were carried out using Student’s t tests, and multiple comparisons were analyzed by repeated measures ANOVA using statistical software GraphPad Instat (San Diego, CA). Log concentration-response curves were analyzed by regression analysis over the linear portion of the curves. All values are expressed as the mean ± SEM. In all cases, P < 0.05 was considered statistically significant.

	Results

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The perfused placental lobules used in this study, from pregnant women at term, aged 27.3 ± 0.9 yr (n = 38), had a basal fetal arterial perfusion pressure of 19.6 ± 1.4 mm Hg (n = 38). Submaximal PGF₂ (4 ± 0.7 µmol/L) increased mean perfusion pressure to 100.7 ± 3.1 mm Hg (n = 38; P < 0.001). Human urocortin (0.001–1 nmol/L; n = 8), piscine urotensin 1 (0.001–1 nmol/L; n = 7), and human CRH (0.001–10 nmol/L; n = 8) each caused concentration-dependent relaxation of the fetal placental vasculature, indicated by reversal of the PGF₂-induced vasoconstriction, as shown in Fig. 1. The estimated EC₃₀ values and maximum relaxing activities of the three peptide agonists are given in Table 1. Urocortin was equipotent with urotensin-1 and was approximately 25 times (95% confidence limits, 19–34) more potent than CRH in causing vasodilatation. As shown in Fig. 2, in the presence of the CRH receptor antagonist -helical CRH-(9–41) (0.2 nmol/L), the concentration-response curves for urocortin (Fig. 2A), urotensin-1 (Fig. 2B) and CRH (Fig. 2C) were shifted to the right and significantly attenuated. In comparison to control experiments, pretreatment with -helical CRH-(9–41) had no appreciable effect on the concentration of PGF₂ (3.3 ± 0.6 µmol/L) used or the subsequent induced submaximal increase in perfusion pressure (92.1 ± 4.2 mm Hg; n = 15; P > 0.05).

View larger version (19K): [in this window] [in a new window]   Figure 1. Vasodilator effects of urocortin (•), urotensin-1 (), and CRH () during perfusion of the isolated placental cotyledon. Data are expressed as the mean reversal of the constriction (percent change in perfusion pressure) induced by PGF2 (0.5–20 µmol/L), and vertical lines indicate the SEM (n = 7–8).

View this table: [in this window] [in a new window]   Table 1. Comparison of the EC30 values (nanomoles per L) and maximum dilator responses (percent relaxation) of urocortin, urotensin-1, and CRH in the human fetal placental vasculature, preconstricted with PGF2 (0.5–20 µmol/L)

View larger version (13K): [in this window] [in a new window]   Figure 2. Comparison of the vasodilator actions of urocortin (A), urotensin-1 (B), or CRH (C) in the absence () or presence (•) of the CRH receptor antagonist -helical CRH-(9–41) (0.2 nmol/L) during perfusion of the isolated placental cotyledon. All values are expressed as the mean reversal of the constriction (percent change in perfusion pressure) induced by PGF2 (0.5–20 µmol/L), and vertical lines indicate ±SEM (n = 5–8). *, P < 0.05; **, P < 0.01 [significantly different from agonist control curve ()].

	Discussion

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2

Urocortin and urotensin-1 are found in mammals and bony fishes, respectively, and show significant amino acid sequence identity with CRH. The latter is not only released from hypothalamic neurons as a neurosecretory pituitary hormone in mammals, but also from the placenta of the higher primates, including humans. CRH is also found, like urocortin (12), in the syncytiotrophoblast of the human placenta (14). We have shown that CRH is a placentally released autacoid (15) involved in the maintenance of the low fetal placental vascular resistance (11, 16). CRH, at concentrations comparable with maternal and fetal plasma levels, is one of the most potent fetal vessel dilators yet discovered, being approximately 50 times more potent than prostacyclin (10). The present study demonstrates for the first time that urocortin is a potent vasodilator in the human fetal vasculature of the placenta, being more potent than CRH. These findings are similar to those in the rat showing urocortin to be the most potent inducer of skin vasodilatation (17). The recent identification of urocortin in the human placenta raises the possibility that the placenta may be capable of expressing a family of related peptides (12) that may be important in the control of fetal placental blood flow.

The in vitro relaxing action of CRH and structurally related ligands in the fetal placental vasculature appears to be specific for CRH receptors, as the CRH antagonist, -helical CRH-(9–41) attenuated the induced vasodilator responses. Interestingly, the effective concentration of -helical CRH-(9–41) that we used (0.2 nmol/L) has been reported to cause selective antagonism of CRH₂ receptors (18). Furthermore, the rank order of agonist potency in the fetal placental vasculature was urocortin = urotensin-1 >> CRH, which was similar to previous binding studies using stably transfected CHO cells expressing CRH₂ receptors (2) and in cAMP accumulation studies in COS-M6 cells transfected with CRH₂ receptors (1). By contrast, urocortin has been shown to be equipotent with urotensin-1 and CRH in stimulating cAMP levels in cells transfected with CRH₁ receptors (1, 5, 6). Thus, our data suggest that the receptor mediating vasodilator responses to urocortin and related peptides in the perfused placenta resembles the CRH₂ subtype. Other peripheral vascular effects of urocortin and related peptides in the perivasculature of the heart (18, 19, 20) and the mesenteric circulation (21) also appear to be mediated by CRH₂ receptors. In addition, CRH₂ receptors have been localized in cerebral arterioles (22), where they have been hypothesized to modulate cerebral blood flow (5).

In conclusion, our results indicate that urocortin and related peptides pharmacologically reduce fetal-placental vascular resistance via CRH₂-like receptors. As the fetal vessels of the human placenta are not innervated, control of blood flow in this vascular bed is partly dependent on locally produced and circulating vasoactive factors (13), which may include urocortin and CRH. The importance of urocortin in modulating placental vascular resistance in vivo remains unclear. Nevertheless, our data suggest that CRH₂ receptor agonists may provide a lead toward the development of novel vasodilators in this important vascular bed.

	Acknowledgments

 
We gratefully acknowledge the cooperation of the patients, nurses, and medical staff of the Division of Obstetrics and Gynecology, John Hunter Hospital, in obtaining placentas. We also thank Prof. Ed Wei, University of California (Berkeley, CA), for the generous gift of human urocortin.

	Footnotes

 
¹ This work was supported by the National Health and Medical Research Council of Australia (Grant 970802), the University of Newcastle Research Management Committee (Grants 45/200/605 and 45/200/615), and a travel grant (to I.M.L.) from the International Society of Endocrinology to present part of this work at the 10th International Congress of Endocrinology, San Francisco, CA.

Received May 1, 1998.

Revised August 10, 1998.

Accepted September 9, 1998.

	References

Top Abstract Introduction Subjects and Methods Results Discussion References

 

1. Vaughan J, Donaldson C, Bittencourt J, et al. 1995 Urocortin, a mammalian neuropeptide related to fish urotensin 1 and to corticotropin-releasing factor. Nature. 378:287–292.[CrossRef][Medline]
2. Donaldson CJ, Sutton SW, Perrin MH, et al. 1996 Cloning and characterisation of human urocortin. Endocrinology. 137:2167–2170.[Abstract]
3. Lederis K, Letter A, McMaster D, Moore G, Schlesinger D. 1982 Complete amino acid sequence of urotensin 1, a hypotensive and corticotropin-releasing peptide from Catostomus. Science. 218:162–164.[Abstract/Free Full Text]
4. Lederis K, Fryer J, Rivier J, et al. 1985 Neurohormones from fish tails. Part II: Actions of urotensin 1 in mammals and fishes. In: Greep RO, ed. Recent progress in hormone research. San Diego: Academic Press; vol 41:553–576.
5. Chalmers DT, Lovenberg TW, Grigoriadis DE, Behan DP, De Souza EB. 1996 Corticotrophin-releasing factor receptors: from molecular biology to drug design. Trends Pharmacol Sci. 17:166–172.[CrossRef][Medline]
6. Vale W, Vaughan J, Perrin M. 1997 Corticotropin-releasing factor (CRF) family of ligands and their receptors. Endocrinologist. 7(Suppl 1):S3–S9.
7. Dieterich KD, Lehnert H, De Souza EB. 1997 Corticotropin-releasing factor receptors: an overview. Exp Clin Endocrinol Diabetes. 105:65–82.[Medline]
8. Petraglia F, Giardino L, Coukos G, Calza L, Vale W, Genazzani AR. 1990 Corticotropin-releasing factor and parturition: plasma and amniotic fluid levels and placental binding sites. Obstet Gynecol. 75:784–789.[Abstract/Free Full Text]
9. Saeed BO, Weightman DR, Self CH. 1997 Characterization of corticotropin-releasing hormone binding sites in the human placenta. J Receptor Signal Transduction Res. 17:647–666.[Medline]
10. Clifton VL, Read MA, Leitch IM, Boura ALA, Robinson PJ, Smith, R. 1994 Corticotrophin-releasing hormone-induced vasodilation in the human fetal placental circulation. J Clin Endocrinol Metab. 79:666–669.[Abstract]
11. Clifton VL, Read MA, Leitch IM, et al. 1995 Corticotrophin-releasing hormone-induced vasodilation in the human fetal placental circulation: involvement of the nitric oxide-cyclic guanosine 3',5'-monophosphate-mediated pathway. J Clin Endocrinol Metab. 80:2888–2893.[Abstract/Free Full Text]
12. Petraglia F, Florio P, Gallo R, et al. 1996 Human placenta and fetal membranes express human urocortin mRNA and peptide. J Clin Endocrinol Metab. 81:3807–3810.[Abstract]
13. Boura ALA, Walters WAW, Read MA, Leitch IM. 1994 Autacoids and control of human placental blood flow. Clin Exp Pharmacol Physiol. 21:737–748.[Medline]
14. Riley SC, Walton JC, Herlick JM, Challis JRG. 1991 The localization and distribution of corticotropin-releasing hormone in the human placenta and fetal membranes throughout gestation. J Clin Endocrinol Metab. 72:1001–1007.[Abstract]
15. Roe C, Leitch IM, Boura ALA, Smith R. 1996 Nitric oxide regulation of corticotrophin-releasing hormone release from the human perfused placenta in vitro. J Clin Endocrinol Metab. 81:763–769.[Abstract]
16. Leitch IM, Roe CM, Walters WAW, Smith R, Boura ALA. 1997 Effect of the L-arginine-nitric oxide pathway on human placental vascular tone and corticotropin-releasing hormone secretion. Hyperten Preg. 16:367–378.
17. Theoharides TC, Boucher W, Singh L, Pang X. Urocortin is a potent inducer of skin mast cell activation and vasodilation: implications for stress-induced atopic diseases [Abstract OR18–1]. Proc of the 79th Annual Meet of The Endocrine Soc. 1997; 89.
18. Kishimoto T, Pearse R, Lin C, Rosenfeld M. 1995 A sauvagine/corticotropin-releasing factor receptor expressed in heart and skeletal muscle. Proc Natl Acad Sci USA. 92:2969–2973.[Abstract/Free Full Text]
19. Perrin MH, Donaldson CJ, Chen R, et al. 1995 Identification of a second CRF receptor gene and characterization of a cDNA expressed in the heart. Proc Natl Acad Sci USA. 92:2969–2973.
20. Stenzel P, Kesterson R, Yeung W, Cone RD, Rittenberg MB, Stenzel-Poore MP. 1995 Identification of a novel murine receptor for corticotropin-releasing hormone expressed in the heart. Mol Endocrinol. 9:637–645.[Abstract]
21. Rohde E, Furket J, Fechner K, et al. 1996 Corticotropin-releasing hormone (CRH) receptors in the mesenteric small arteries of rats resemble the (2)-subtype. Biochem Pharmacol. 52:829–833.[CrossRef][Medline]
22. Chalmers DT, Lovenberg TW, De Souza EB. 1995 Localization of novel corticotropin-releasing factor receptor (CRF2) mRNA expression to specific subcortical nuclei in rat brain: comparison with CRF1 receptor mRNA expression. J Neurosci. 15:6340–6350.[Abstract/Free Full Text]

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