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Abstract
Ovulation is dependent upon numerous factors mediating follicular growth, vascularization, and ultimately oocyte release via follicle rupture. Endothelin-2 (EDN2) is a potent vasoconstrictor that is transiently produced prior to follicle rupture by granulosa cells of periovulatory follicles and induces ovarian contraction. To determine the role of Edn2 expression, surgical transplant and novel conditional knockout mice were super-ovulated and analyzed. Conditional knockout mice utilized a new iCre driven by the Esr2 promoter to selectively remove Edn2. Follicle rupture and fertility were significantly impaired in the absence of ovarian Edn2 expression. When ovaries of Edn2KO mice were transplanted in wild type recipients, significantly more corpora lutea containing un-ovulated oocytes were present after hormonal stimulation (1.0 vs. 5.4, p = 0.010). Following selective ablation of Edn2 in granulosa cells, Esr2-Edn2KO dams had reduced oocytes ovulated (3.8 vs. 16.4 oocytes/ovary) and smaller litters (4.29 ± l.02 vs. 8.50 pups/dam). However, the number of pregnancies per pairing was not different and the reproductive axis remained intact. Esr2-Edn2KO ovaries had a higher percentage of antral follicles and fewer corpora lutea; follicles progressed to the antral stage but many were unable to rupture. Conditional loss of endothelin receptor A in granulosa cells also decreased ovulation but did not affect fecundity. These data demonstrate that EDN2-induced intraovarian contraction is a critical trigger of normal ovulation and subsequent fecundity.
Highlights
Endothelin-2 (Edn2) encodes a short 21-amino acid peptide[1]
EDN2 global knockout (Edn2KO) mice were noticeably smaller by post-natal day 6 (PND6) despite heat/nutritional supplementation with Peptamen (Nestle), which suggests that observed growth retardation was due to starvation or early postnatal developmental defects (Fig. 1A)
In Edn2KO mice, systemic loss of Edn[2] causes early juvenile death likely through starvation, though ovarian development is only slightly affected by PND6
Summary
Endothelin-2 (Edn2) encodes a short 21-amino acid peptide[1]. EDN2 is one of three similar isoforms in the body that act through two endothelin receptors (EDNRA and EDNRB)[2, 3]. Edn[2] mRNA is expressed in murine granulosa cells of mature ovarian follicles immediately prior to ovulation for approximately two hours[3, 5,6,7] This period corresponds to ovulation and early corpus luteum (CL) formation in the mouse. Global Edn[2] loss is lethal to juveniles at approximately eight days of age, and organ transplant to healthy WT recipients was used to overcome this barrier to generate a mouse model that lacks Edn[2] in the ovary only This ovary-specific Edn[2] ablation was achieved by transplanting ovaries of global Edn2KO to the kidney capsule of ovariectomized wild type (WT) mice to create a novel mouse model for examining the role of EDN2 in follicular development and ovulation
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