Loss of function of endothelin-2 leads to reduced ovulation and CL formation.

Joseph A Cacioppo,Sang Wook Oh,Masashi Yanagisawa,Chemyong Ko,Jongki Cho,Hey-Young Kim,Po-Ching Patrick Lin,Jae-Wook Jeong

doi:10.1371/journal.pone.0096115

Abstract

Endothelin-2 (EDN2), a potent vasoconstrictive peptide, is transiently produced by periovulatory follicles at the time of ovulation when corpus luteum (CL) formation begins. EDN2 induces contraction of ovarian smooth muscles ex vivo via an endothelin receptor A-mediated pathway. In this study, we aimed to determine if EDN2 is required for normal ovulation and subsequent CL formation in?vivo. In the ovaries of a mouse model that globally lacks the Edn2 gene (Edn2 knockout mouse; Edn2KO), histology showed that post-pubertal Edn2KO mice possess follicles of all developmental stages, but no corpora lutea. When exogenous gonadotropins were injected to induce super-ovulation, Edn2KO mice exhibited significantly impaired ovulation and CL formation compared to control littermates. Edn2KO ovaries that did ovulate in response to gonadotropins did not contain histologically and functionally identifiable CL. Intra-ovarian injection of EDN2 peptide results suggest partial induction of ovulation in Edn2KO mice. Endothelin receptor antagonism in wild type mice similarly disrupted ovulation, CL formation, and progesterone secretion. Overall, this study suggests that EDN2 is necessary for normal ovulation and CL formation.

Highlights

Ovulation, a rupture of the ovarian surface and expulsion of the oocyte and cumulus cells from a mature follicle, is a central event in female reproduction that results in the formation of the corpus luteum (CL)
Heterozygous littermates displayed no significant difference in the number of oocytes ovulated or in serum progesterone levels after induced ovulation compared to wild type (WT) mice, nor any other morphological differences, and were used as controls for Edn2KO mice for the remainder of this study (Table 1)
We hypothesized that EDN2 triggers oocyte expulsion and is concurrently necessary for CL formation

Summary

Introduction

A rupture of the ovarian surface and expulsion of the oocyte and cumulus cells from a mature follicle, is a central event in female reproduction that results in the formation of the corpus luteum (CL). Cross talk between circulating hormones and local cellular components in the hypothalamic-anterior pituitary-ovarian (HPO) axis is required to regulate oocyte production and rupture during ovulation [1,2]. The ruptured follicle transforms into a CL, the primary source of progesterone that is required for embryo implantation and pregnancy maintenance [7]. A highly condensed vascular capillary network is established in the forming CL within hours of ovulation [10]. This newly formed luteal vasculature functions as a route for secreting progesterone and for supplying nutrients, oxygen, and steroid hormone precursors to the CL. As CL formation is successive with ovulation and CL-secreted hormones are necessary for pregnancy, molecular mechanisms involved in CL formation and function are of interest in infertility therapy and contraceptive development

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