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Vertebrate reproductive science and technology
RESEARCH ARTICLE (Open Access)

Production and binding of endothelin-2 (EDN2) in the rat ovary: endothelin receptor subtype A (EDNRA)-mediated contraction

Phillip J. Bridges A , Misung Jo B , Linah Al Alem A , Giyoun Na A , Wen Su C , Ming C. Gong C , Myoungkun Jeoung A and CheMyong Ko A D E
+ Author Affiliations
- Author Affiliations

A Division of Clinical and Reproductive Sciences, University of Kentucky, Lexington, KY 40536, USA.

B Department of Obstetrics and Gynecology, University of Kentucky, Lexington, KY 40536, USA.

C Department of Physiology, University of Kentucky, Lexington, KY 40536, USA.

D Department of Biology, University of Kentucky, Lexington, KY 40536, USA.

E Corresponding author. Email: cko2@uky.edu

Reproduction, Fertility and Development 22(5) 780-787 https://doi.org/10.1071/RD09194
Submitted: 18 August 2009  Accepted: 11 November 2009   Published: 7 April 2010

Abstract

Endothelin-2 (EDN2)-mediated contraction has been proposed as a final mechanical signal facilitating ovulation. The objectives herein were to determine (1) whether ovarian endothelins were increased before ovulation; (2) whether a specific endothelin-converting enzyme (ECE) was mediating their production; (3) which receptor was facilitating ovarian contraction; and (4) whether receptor-specific antagonism affected ovulation. Follicular development was induced in immature rats with 10 IU pregnant mare serum gonadotrophin (PMSG) and the ovulatory cascade was initiated 48 h later with 10 IU human chorionic gonadotrophin (hCG). In Experiment 1, an immunoassay revealed that the ovarian concentration of endothelin peptide was increased 7-fold 12 h after hCG when compared with 48 h after PMSG (P < 0.05). In Experiment 2, real-time PCR indicated that mRNA for Ece1, but not Ece2, was increased in granulosa cells collected 12 h after hCG when compared with those collected before the ovulatory stimulus (P < 0.05). In Experiment 3, isometric tension analysis revealed that the contractile effect of EDN2 was mediated by endothelin receptor A (EDNRA), not B (EDNRB). In Experiment 4, no effect was observed on the rate of ovulation when rats were treated with an antagonist specific to EDNRA (BQ123) or EDNRB (BQ788), or when mice were treated with BQ123, BQ788 or BQ123 + BQ788. In conclusion, endothelin peptide is produced before ovulation and the contractile action of EDN2 within the ovary is facilitated via EDNRA. In addition, findings of this study indicate synergistic interactions among contractile factors affect ovulatory outcome, while the role of EDNRB alone in the process of ovulation requires further investigation.

Additional keywords: constriction, ovulation, rupture.


Acknowledgements

This work was supported by grant RO1HD052694 (C.K.), K12 DA014040 (P.B.) and P20 RR15592 (P.B. and C.K.) from the National Institutes of Health.


References

Acosta, T. J. , Berisha, B. , Ozawa, T. , Sato, K. , Schams, D. , and Miyamoto, A. (1999). Evidence for a local endothelin–angiotensin–atrial natriuretic peptide system in bovine mature follicles in vitro: effects on steroid hormones and prostaglandin secretion. Biol. Reprod. 61, 1419–1425.
CrossRef | PubMed | CAS |

Al-Alem, L. , Bridges, P. J. , Su, W. , Gong, M. C. , Iglarz, M. , and Ko, C. (2007). Endothelin-2 induces oviductal contraction via endothelin receptor subtype A in rats. J. Endocrinol. 193, 383–391.
CrossRef | PubMed | CAS |

Alexander, M. J. , Mahoney, P. D. , Ferris, C. F. , Carraway, R. E. , and Leeman, S. E. (1989). Evidence that neurotensin participates in the central regulation of the preovulatory surge of luteinizing hormone in the rat. Endocrinology 124, 783–788.
CrossRef | PubMed | CAS |

Chester, A. H. , Azam, R. , Felkin, L. E. , George, R. , and Brand, N. (2007). Correlation between vascular responsivensss and expression of novel transcripts of the ETA-receptor in human vascular tissue. Vascul. Pharmacol. 46, 181.
CrossRef | PubMed | CAS |

Chun, S. Y. , Popliker, M. , Reich, R. , and Tsafriri, A. (1992). Localization of preovulatory expression of plasminogen activator inhibitor type-1 and tissue inhibitor of metalloproteinase type-1 mRNAs in the rat ovary. Biol. Reprod. 47, 245–253.
CrossRef | PubMed | CAS |

Continho, E. M. , and Maia, H. S. (1971). The contractile response of the human uterus, fallopian tubes, and ovary to prostaglandins in vivo. Fertil. Steril. 22, 539–543.
PubMed |

Coutinho, E. M. (1974). Ovarian contractility and ovulation. Res. Reprod. 6, 3–4.
PubMed | |  CAS |

Curry, T. E. , and Smith, M. F. (2006). Impact of extracellular matrix remodeling on ovulation and the folliculo–luteal transition. Semin. Reprod. Med. 24, 228–241.
CrossRef | PubMed | CAS |

Debeljuk, L. (2006). Tachykinins and ovarian function in mammals. Peptides 27, 736.
CrossRef | PubMed | CAS |

Espey, L. L. , and Lipner, H. (1963). Measurements of intrafollicular pressures in the rabbit ovary. Am. J. Physiol. 205, 1067–1072.
PubMed | |  CAS |

Flores, J. A. (2000). Gene expression of endothelin-1 in the porcine ovary: follicular development. Biol. Reprod. 63, 1377–1382.
PubMed | |  CAS |

Gómez, R. , Simón, C. , Remohí, J. , and Pellicer, A. (2003). Administration of moderate and high doses of gonadotropins to female rats increases ovarian vascular endothelial growth factor (VEGF) and VEGF Receptor-2 expression that is associated to vascular hyperpermeability. Biol. Reprod. 68, 2164–2171.
CrossRef | PubMed |

Guo, Z. , Su, W. , Ma, Z. , Smith, G. M. , and Gong, M. C. (2003). Ca2+-independent phospholipase A2 is required for agonist-induced Ca2+ sensitization of contraction in vascular smooth muscle. J. Biol. Chem. 278, 1856–1863.
CrossRef | PubMed | CAS |

Hasan, S. , Hosseini, G. , Princivalle, M. , Dong, J.-C. , Birsan, D. , Cagide, C. , and de Agostini, A. I. (2002). Coordinate expression of anticoagulant heparan sulfate proteoglycans and serine protease inhibitors in the rat ovary: a potent system of proteolysis control. Biol. Reprod. 66, 144–158.
CrossRef | PubMed | CAS |

Hellberg, P. , Larson, L. , Olofsson, J. , Hedin, L. , and Brannstrom, M. (1991). Stimulatory effects of bradykinin on the ovulatory process in the in vitro-perfused rat ovary. Biol. Reprod. 44, 269–274.
CrossRef | PubMed | CAS |

Hoang, M. V. , and Turner, A. J. (1997). Novel activity of endothelin-converting enzyme: hydrolysis of bradykinin. Biochem. J. 327(Pt 1), 23–26.
PubMed | |  CAS |

Johnson, G. D. , Stevenson, T. , and Ahn, K. (1999). Hydrolysis of peptide hormones by endothelin-converting enzyme-1. A comparison with neprilysin. J. Biol. Chem. 274, 4053–4058.
CrossRef | PubMed | CAS |

Kitajima, Y. , Endo, T. , Manase, K. , Nishikawa, A. , Shibuya, M. , and Kudo, R. (2004). Gonadotropin-releasing hormone agonist administration reduced vascular endothelial growth factor (VEGF), VEGF receptors, and vascular permeability of the ovaries of hyperstimulated rats. Fertil. Steril. 81, 842.
CrossRef | PubMed | CAS |

Ko, C. , Gieske, M. C. , Al-Alem, L. , Hahn, Y. , Su, W. , Gong, M. C. , Iglarz, M. , and Koo, Y. (2006). Endothelin-2 in ovarian follicle rupture. Endocrinology 147, 1770–1779.
CrossRef | PubMed | CAS |

Liu, Y. X. , Peng, X. R. , Chen, Y. J. , Carrico, W. , and Ny, T. (1997). Prolactin delays gonadotrophin-induced ovulation and down-regulates expression of plasminogen-activator system in ovary. Hum. Reprod. 12, 2748–2755.
CrossRef | PubMed | CAS |

Livak, K. J. , and Schmittgen, T. D. (2001). Analysis of relative gene expression data using real-time quantitative PCR and the 2–ΔΔCT method. Methods 25, 402–408.
CrossRef | PubMed | CAS |

Masaki, T. , Ninomiya, H. , Sakamoto, A. , and Okamoto, Y. (1999). Structural basis of the function of endothelin receptor. Mol. Cell. Biochem. 190, 153–156.
CrossRef | PubMed | CAS |

Matousek, M. , Carati, C. , Gannon, B. , and Brannstrom, M. (2001). Novel method for intrafollicular pressure measurements in the rat ovary: increased intrafollicular pressure after hCG stimulation. Reproduction 121, 307–314.
CrossRef | PubMed | CAS |

Miyabayashi, K. , Shimizu, T. , Kawauchi, C. , Sasada, H. , and Sato, E. (2005). Changes of mRNA expression of vascular endothelial growth factor, angiopoietins and their receptors during the periovulatory period in eCG/hCG-treated immature female rats. J. Exp. Zool. A Comp. Exp. Biol. 303A, 590–597.
CrossRef | CAS |

O’Shea, J. D. , and Phillips, R. E. (1974). Contractility in vitro of ovarian follicles from sheep, and the effect of drugs. Biol. Reprod. 10, 370–379.
CrossRef | PubMed | CAS |

Palanisamy, G. S. , Cheon, Y.-P. , Kim, J. , Kannan, A. , Li, Q. , Sato, M. , Mantena, S. R. , Sitruk-Ware, R. L. , Bagchi, M. K. , and Bagchi, I. C. (2006). A novel pathway involving progesterone receptor, endothelin-2, and endothelin receptor B controls ovulation in mice. Mol. Endocrinol. 20, 2784–2795.
CrossRef | PubMed | CAS |

Palti, Z. , and Freund, M. (1972). Spontaneous contractions of the human ovary in vitro. J. Reprod. Fertil. 28, 113–115.
CrossRef | PubMed | CAS |

Priddy, A. R. , and Killick, S. R. (1993). Eicosanoids and ovulation. Prostaglandins Leukot. Essent. Fatty Acids 49, 827–831.
CrossRef | PubMed | CAS |

Rondell, P. (1964). Follicular pressure and distensibility in ovulation. Am. J. Physiol. 207, 590–594.
PubMed | |  CAS |

Schmidt, G. , Kannisto, P. , Owman, C. , and Walles, B. (1987). Characterization of histamine receptors mediating contraction and relaxation of the ovarian follicle wall. Int. J. Fertil. 32, 399–406.
PubMed | |  CAS |

Schroeder, P. C. , and Talbot, P. (1982). Intrafollicular pressure decreases in hamster preovulatory follicles during smooth muscle cell contraction in vitro. J. Exp. Zool. 224, 417–426.
CrossRef | PubMed | CAS |

Smith, C. , and Perks, A. M. (1984). The effects of bradykinin on the contractile activity of the isolated rat ovary. Acta Endocrinol. (Copenh.) 106, 387–392.
PubMed | |  CAS |

Talbot, P. , and Chacon, R. S. (1982). In vitro ovulation of hamster oocytes depends on contraction of follicular smooth muscle cells. J. Exp. Zool. 224, 409–415.
CrossRef | PubMed | CAS |

Tedeschi, C. , Hazum, E. , Kokia, E. , Ricciarelli, E. , Adashi, E. Y. , and Payne, D. W. (1992). Endothelin-1 as a luteinization inhibitor: inhibition of rat granulosa cell progesterone accumulation via selective modulation of key steroidogenic steps affecting both progesterone formation and degradation. Endocrinology 131, 2476–2478.
CrossRef | PubMed | CAS |

Tirapelli, C. R. , Casolari, D. A. , Montezano, A. C. , Yogi, A. , Tostes, R. C. , Legros, E. , D’Orleans-Juste, P. , Lanchote, V. L. , Uyemura, S. A. , and de Oliveira, A. M. (2006). Ethanol consumption enhances endothelin-1-induced contraction in the isolated rat carotid. J. Pharmacol. Exp. Ther. 318, 819–827.
CrossRef | PubMed | CAS |

Turner, A. J. , and Murphy, L. J. (1996). Molecular pharmacology of endothelin-converting enzymes. Biochem. Pharmacol. 51, 91.
CrossRef | PubMed | CAS |

Virutamasen, P. , Smitasiri, Y. , and Fuchs, A. R. (1976). Intraovarian pressure changes during ovulation in rabbits. Fertil. Steril. 27, 188–196.
PubMed | |  CAS |

Yoshioka, S. , Fujiwara, H. , Yamada, S. , Tatsumi, K. , Nakayama, T. , Higuchi, T. , Inoue, T. , Maeda, M. , and Fujii, S. (1998). Endothelin-converting enzyme-1 is expressed on human ovarian follicles and corpora lutea of menstrual cycle and early pregnancy. J. Clin. Endocrinol. Metab. 83, 3943–3950.
CrossRef | PubMed | CAS |


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