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Urocortin Stimulates Placental Adrenocorticotropin and Prostaglandin Release and Myometrial Contractility in Vitro

Department of Surgical Sciences (F.P.), Chair of Obstetrics and Gynecology, University of Udine, 33100 Udine, Italy; Department of Reproductive Medicine and Child Development (P.F., S.L., A.R.G.), Section of Obstetrics and Gynecology, University of Pisa, 56100 Pisa, Italy; Department of Obstetrics and Gynecology (C.B., L.M.), University of Torino, 10024 Torino, Italy; Auxologic Institute (A.M.D.B.), University of Milano, Milano, Italy; Department of Surgery (C.T., E.P.), Section of Gynecological Endocrinology, University of Tor Vergata, 00133 Rome, Italy; and The Clayton Foundation Laboratories for Peptide Biology (W.V.), Salk Institute, La Jolla, California

Address all correspondence and requests for reprints to: Felice Petraglia, M.D., Department of Surgical Sciences, Chair of Obstetrics and Gynecology, University of Udine, Piazzale S. Maria della Misericordia, 33100 Udine, Italy. E-mail: felice.petraglia{at}dsc.uniud.it

	Abstract

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Urocortin is a new member of the CRF family. Multiple biological effects for urocortin have been shown in rats and in some in vitro models, showing a modulatory role in hormonal and behavioral functions. Human placenta expresses urocortin, but no information is available on the possible local biological actions. The aim of the present study was to evaluate the effect of urocortin on placental ACTH and prostaglandin (PG) secretion, as well as on myometrial contractility.

Various in vitro models were used. For investigating the effect of urocortin on ACTH release, primary cultures of human trophoblast cells were used. Culture media, collected before and after 3 h exposure to different doses of urocortin and ACTH, were measured by RIA. Trophoblast tissue explants were incubated for 24 h in the presence of increasing doses of urocortin, and prostaglandin E2 (PGE2) levels were measured by RIA. Strips of myometrial tissue were incubated in an organ bath and connected to an isometric smooth-muscle transducer in the presence of urocortin, with or without prostaglandin F2 (PGF2). In all these experiments, the effect of astressin (a CRF receptor antagonist) on urocortin-induced actions and the effect of equimolar doses of CRF were evaluated.

A dose-related increase of trophoblast ACTH or PGE2 was induced by urocortin, whereas astressin inhibited urocortin-stimulated ACTH or PGE2 release. Equimolar doses of CRF showed a similar effect on both ACTH and PGE2. Urocortin increased PGF2-induced myometrial contractility, and this effect was completely abolished by the addition of astressin.

The present study showed that human urocortin stimulates placental secretion of ACTH and PGE2, and modulates myometrial contractility, suggesting a role for this peptide in placental and intrauterine CRF pathways.

	Introduction

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UROCORTIN is a newly discovered peptide recognized as member of the CRF family because it shares some biochemical and biological characteristics with CRF (1, 2). It has been cloned and localized to chromosome 2 and is expressed in human pituitary (3) and placenta (4). Human urocortin binds with high affinity to CRF receptors and CRF-binding protein (CRF-BP) (5, 6). Multiple biological effects for urocortin have been shown: it stimulates the release of ACTH from cultured rat pituitary cells (1), induces a significant and prolonged elevation of plasma ACTH levels in rat (2); suppresses feeding behavior in fasted rats (7), decreases mean arterial blood pressure in sheep (8), and inhibits edema caused by thermal injury in rats (9).

Recent findings revealed that human placenta and gestational related tissues (amnion, chorion, decidua) express human urocortin messenger RNA (mRNA) gene and localize immunoreactive urocortin (4), but no information is available on the possible local biological actions. Conversely, it is well established that placental CRF has several biological effects within the same tissue or in the closest anatomical organs (fetal membranes and myometrium) (10, 11). In fact, CRF increases ACTH (12) or PG (13) release from cultured placental cells and increases placental vasodilation (14) and myometrial contractility (15). These effects are mediated by specific CRF receptors, localized on trophoblast and myometrial cells (16, 17, 18). The biological effects of CRF on placenta, decidua, and myometrium are modulated by CRF-BP (19).

The aim of the present study was to investigate the possible effect of urocortin on placental hormone secretion, as well as on myometrial contractility. In each experiment, a synthetic CRF receptor antagonist, astressin, was used to reverse the urocortin effect.

	Materials and Methods

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Tissue collection

For placental cultures (n = 5) and trophoblast tissue explants (n = 3), placentas were collected, from pregnant women at term (38–40 weeks) undergoing elective cesarean sections before the onset of labor, for routine indications.

For uterine contractility evaluation, myometrial strips were obtained from the upper edge of the uterine incision during elective cesarean sections (n = 24), between 38 and 40 weeks, performed before the onset of labor.

Gestational age was calculated by the date of the last menstrual period and was confirmed by ultrasonographic examination. Permission of the Human Investigation Committee was granted for the various experiments, and patients gave an informed consent.

Placental cell culture

Isolation of human placental cells was performed as previously described (20), using pieces of placental cotyledons (free of vessels, membranes, and stroma). Culture of freshly isolated trophoblast was carried out in 6-well plates (0.75–1.5 x 10⁶ cells/well) with supplemented DMEM containing 20% FCS, 4 mmol/L glutamine, and 50 µg/mL gentamicin at 37 C under humidified 5% CO₂. The experiments were done after 48–72 h incubation; and before the stimulation, the cells were washed twice with phosphate-buffered saline. Conditioned medium (without FCS, containing 0.1% BSA) was harvested 3 h after addition of human urocortin, or urocortin plus astressin, or CRF. Measurements of ACTH levels were repeated at least three times. The hormone production was maximal after 48–72 h in culture.

Trophoblast tissue explants

Cultures of tissue explants were carried out, following the procedure of Wetzka et al. (21), with slight modifications. Placental samples were cut close to the insertion of the umbilical cord, avoiding fetal membranes and large vessels. Tissues were placed in ice-cold saline sterile solution, washed several times in the same solution to remove blood and clots, weighed, and put into dishes containing 5 mL of culture medium RPMI 1640 (Gibco BRL, Grand Island, NY) with 10% FCS, penicillin (100 U/mL), and streptomycin (100 g/mL). Tissues were then incubated for 24 h at 37 C in an atmosphere of 95% O₂-5% CO₂.

Each sample was divided into eight specimens, which were incubated in duplicate in the presence of urocortin, or urocortin plus astressin, or astressin, or CRF. The calcium ionophore A23187 (Sigma Chemical Co., St. Louis, MO) was used as positive control, and controls (0.9% NaCl saline infusion served as negative control) were incubated in the absence of the above substances. Conditioned medium was collected, centrifuged at 3000 rpm to eliminate any cell debris, and stored at -80 C until PGE2 assay. Tissue viability was checked by the lactic dehydrogenase assay, as previously reported (22).

RIA

ACTH concentrations in culture medium were measured by a specific RIA kit (Eurogenix, London, UK) and expressed as pg/mL secreted per dish. Each sample was assayed in triplicate. The assay sensitivity was 1 pg/mL; inter- and intraassay coefficients of variation were 5% and 3%, respectively.

PGE2 was measured in triplicate in all culture media directly by an RIA kit (NEN Du Pont De Nemours, Cologno Monzese, Italy), as previously reported (23). The limit of sensitivity for the PGE2 assay was 13 pg/mL. The intra- and interassay coefficients of variation for the PGE2 assay were 8 and 10%, respectively.

Myometrial contractility

Immediately after surgical excision, muscle specimens (approximately 2 cm, with a cross-sectional area of 0.5 cm²) were placed in 20 mL of chilled (4 C), oxygenated standard Tyrode’s solution (pH 7.4) containing (in mmol/L) sodium chloride (0.5), calcium chloride (2.0), potassium chloride (4.0), glucose (5.5), and N-(2-hydroxy-ethyl)piperazine-N'-ethanesulfonic acid (5.0) and were brought to the laboratory. The samples were then dissected free of connective tissue and cut into small strips (mean wet weight ± SD, 280 ± 150 mg) longitudinally to fiber structure. Two strips from the same muscle preparation were then vertically mounted in a 30-mL two-chamber organ bath (Model 4050; Basile, Comerio, Italy) containing oxygenated Tyrode’s buffer warmed at 37.5 C. Strips were connected to a two-channel isometric smooth-muscle transducer (Unirecord, Basile). The emanating signals were amplified with a strain-gauge preamplifier and reproduced on a two-channel recorder (Gemini, Basile).

Experimental protocol was performed as previously described (15). Specimens with spontaneous contractile activity before stimulation were discarded. In each experiment, a myometrial strip, mounted in one chamber of the organ bath, was used as a control. After each single dose tested, the strip was repeatedly washed with Tyrode’s buffer and equilibrated. In unresponsive cases, the viability of the tissue was tested by adding oxytocin (2.5 mU/mL, 5 nmol/L; Syntocinon, Sandoz Pharmaceuticals Corp., Basel, Switzerland) at the end of the experiment. Specimens that did not respond to oxytocin were discarded.

Human urocortin was dissolved in bidistilled water, and a possible effect on myometrial strips was tested by adding, to one chamber of the organ bath, increasing concentrations.

In a further series of experiments, myometrial strips were stimulated with increasing concentrations of prostaglandin F2 (PGF2). After each stimulation, the uterine specimen was washed, and a higher concentration of PG was added until a contractile response was recorded. At this stage, urocortin or vehicle was added to the chamber of the organ bath, 40 min before the addition of PG. Astressin (10^-9 mol/L) was incubated with one myometrial strip, 10 min before the addition of an equimolar effective concentration of urocortin. The effect of equimolar doses of CRF was also studied.

Statistical analysis

For placental culture (n = 5), each experiment was repeated at least three times. For trophoblast tissue explants (n = 3), each sample was divided into eight specimens and was incubated in duplicate.

For ACTH and PGE2 release from trophoblast cells and tissue cultures, data are expressed as means ± SEM. Statistical analysis was performed using one-way ANOVA, followed by Student-Newman-Keuls for post hoc multiple comparisons among groups. Significance was assumed at the P < 0.05 level.

For the uterine contractility evaluation, each experiment was repeated at least three times, and the results were calculated by measuring the area under the curve of each contraction. The significance of changes was assessed, at the P < 0.05 level, by paired Student’s t test.

	Results

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Effect on ACTH release

Cultured placental cells released ACTH in culture medium (Fig. 1). The addition of CRF or urocortin significantly increased trophoblast ACTH secretion in a dose-dependent manner (P < 0.01) (Fig. 1). No significant difference between CRF- and urocortin-induced ACTH release was observed. Astressin inhibited urocortin-stimulated ACTH release by cultured placental cells (Fig. 1).

View larger version (17K): [in this window] [in a new window]   Figure 1. Effect of urocortin on ACTH release from cultured human placental cells (representative example of a single experiment). Urocortin or CRF significantly increases trophoblast ACTH secretion in a dose-dependent manner. The addition of urocortin significantly inhibits the urocortin-stimulated ACTH release. *, P < 0.01 vs. dose 0.

Explants of unstimulated human placental tissue at term gestation released PGE2 in culture medium. Urocortin stimulated PGE2 release by tissues in a dose-dependent manner (P < 0.01) (Fig. 2, upper panel). Astressin inhibited urocortin-stimulated PGE2 release from placental explants (P < 0.01). The urocortin- and CRF-induced PGE2 release were not significantly different (Fig. 2, lower panel).

View larger version (22K): [in this window] [in a new window]   Figure 2. Panel A, Dose-dependent effect of urocortin on PGE2 release from explants of human placental tissues at term (representative example of a single experiment). *, P < 0.01 vs. dose 0. Panel B, Effect of A23187 (calcium ionophore A23187), CRF, urocortin (Urc), or urocortin plus astressin (Urc + Astr) on PGE2 release from human placental tissues. C, Control tissues. *, P < 0.01 vs. C.

When measured as area under the curve (evaluated as square centimeters) the addition of urocortin did not induce significant changes of myometrial contractility (data not shown). A contractile response to PGF₂ was obtained when the substance reached a final concentration in the organ bath of 0.8 or 1.4 µmol/L (mean ± SEM: 1.40 ± 0.28). A 2-fold increase of the contractility area was found when urocortin was added 40 min before the second effective dose of PGF₂ (mean ± SEM: 2.81 ± 0.28) (P < 0.01) (Fig. 3, upper panel). In the control specimen the addition of saline solution did not show a significant increase in contractile activity when challenged with PGF₂ (mean ± SEM: 2.71 ± 0.24). Addition of astressin completely abolished the effect of urocortin on PGF₂-induced myometrial contractility (Fig. 3, lower panel).

View larger version (19K): [in this window] [in a new window]   Figure 3. A, The response of human myometrial strip to PGE2 is potentiated by urocortin (W = washing); B, myometrial contractions induced by PGE2 and urocortin. The addition of astressin to myometrial strips before urocortin abolishes its effect (representative example of a single experiment).

	Discussion

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2

Therefore, the present data suggest a local site of action for placental urocortin. Indeed, human placenta expresses urocortin mRNA, and immunoreactive urocortin is localized in the same placental cells that contain immunoreactive CRF and CRF-BP (syncytiotrophoblast and fetal membranes) (4, 24, 25).

The effect of human urocortin on placental ACTH release fits with the observation that rat urocortin is a highly potent secretagogue for pituitary ACTH, both in vitro and in vivo (1, 2). Because urocortin is also a product of pituitary cells (3), it probably represents a local modulator of ACTH release, and the same hypothesis may serve for placental urocortin.

Urocortin also stimulates PGE₂ release from trophoblast cells in a dose-dependent manner. This effect, as well as the effect on ACTH, is similar to that exerted by equimolar doses of CRF, suggesting a common receptor for both peptides. Indeed, both the effects on ACTH and PGE2 release are suppressed by astressin, which is a synthetic CRF antagonist, able to bind CRF type 1 and type 2 receptors. The specific binding of astressin to CRF receptors is greater than that of urocortin (26). Even though the major binding sites for urocortin are the type 2 receptors, the evidence that ACTH and PGE2 release induced by CRF or urocortin is similar suggests an involvement of CRF type 1 receptor. In fact, urocortin is equipotent with CRF in stimulating cAMP levels in cells transfected with CRF type 1 receptor (2). Recently, a prevalence of CRF type 1 receptor in syncytiotrophoblast and amnion cells has been shown, indicating the expression of CRF-C variant (27).

Myometrial-induced PGF₂ contractility is increased by urocortin, and completely reversed by astressin, thus confirming that this action also involves CRF receptors. In fact, specific CRF receptors are expressed in human pregnant myometrium (16). The evidence that urocortin modulates myometrial contractility leads us to hypothesize a role for this placental peptide in the modulation of uterine activity in vivo.

A role for urocortin in intraplacental blood flow regulation also has been suggested (28), in agreement with the evidence that CRF is a local mediator of placental endothelial tone (14, 29, 30). An effect on blood vasculation is supported by the observation that urocortin produces in rats a prolonged hypotensive effect when administered iv, hypertension when centrally administered, and a prolonged hypotensive effect after sc administration (7, 8).

The evidence that urocortin affects placental ACTH and PGE2 release and myometrial contractility in vitro lead us to hypothesize a local role for this peptide in the paracrine control of placental hormonogenesis, probably acting throughout the CRF type 1 binding sites.

	Acknowledgments

 
We thank J. Rivier (The Clayton Foundation Laboratories for Peptide Biology, Salk Institute) for gifting human urocortin, human CRF, and astressin.

	Footnotes

 
¹ A Foundation Research Senior Investigator.

Received August 3, 1998.

Revised December 4, 1998.

Accepted January 5, 1999.

	References

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