Why two endothelins and two receptors for ovulation and luteal regulation?

Abstract

The ovary is a dynamic organ that undergoes cyclic structural and functional changes. Structurally, the internal architecture of the ovary constantly changes as follicles grow, rupture and transform into corpora lutea in a cyclical manner. Functionally, a variety of regulatory ovarian hormones are sequentially produced, and eggs are periodically released. As a highly vascularized organ, the ovarian structures and functions change in response to external stimuli that include but are not limited to pituitary gonadotropins. Following stimulation, the ovary synthesizes and releases autocrine and paracrine signals that play unique roles in regulating its function. Recent studies have identified endothelins as local regulators in the ovary that modulate multiple cyclic events, such as follicle growth, steroidogenesis, oocyte maturation, ovulation, corpus luteum formation and luteolysis. Interestingly, in all mammalian species examined to date, a common observation has been made: the ovary produces two pharmacologically similar endothelins (ET-1 and ET-2) but expresses two functionally different endothelin receptors (ET(A) and ET(B)) that often give rise to opposite physiological outcomes following activation by an endothelin. In this review, the physiological significance of the presence of the two ligand-two receptor endothelin system in the ovary will be discussed.

Loss of Function of Endothelin-2 Leads to Reduced Ovulation and CL Formation

“…Incorrect genotyping was ruled out and, in consideration of the established ability of EDN2 to induce contraction in ovarian tissues [13], [16], it is speculated that contraction might be induced in these Edn2KO ovaries by some molecules(s) such as prostaglandins that are produced in the ovary [42], [43], triggering oocyte expulsion. Both of these Edn2KO mice had low serum progesterone concentration, strengthening the assumption that EDN2 is necessary for CL formation even when oocyte release occurs.…”

“…EDN2 is the least well studied member of the Endothelin system, which consists of three isoforms of 21-residue peptides (EDN1, EDN2, EDN3), two G-protein coupled receptors (ET A and ET B ), and two endothelin-converting enzymes (ECE-1 and ECE-2) [15], [16]. Little is known about what factors other than hypoxia are involved in Edn2 induction [14], [17], [18].…”

Granulosa cell endothelin-2 expression is fundamental for ovulatory follicle rupture

“…Previous work by Bridges et al . using receptor antagonists support that EDNRA is the critical receptor involved in ovulation: EDN2-mediated contraction was reduced by a specific EDNRA antagonist but not by a specific EDNRB antagonist 3, 11 . Additionally, mice that conditionally lack EDNRB demonstrate no reproductive deficits and instead give birth to more pups per litter and produce more corpora lutea 30 .…”

“…EDN2 is one of three similar isoforms in the body that act through two endothelin receptors (EDNRA and EDNRB) 2, 3 . Edn2 is expressed in the gastrointestinal tract, prostate, skin, testes, and notably is known to be transiently expressed in the stimulated rodent and human ovary 4 .…”

“…Edn2 is expressed in the gastrointestinal tract, prostate, skin, testes, and notably is known to be transiently expressed in the stimulated rodent and human ovary 4 . Edn2 mRNA is expressed in murine granulosa cells of mature ovarian follicles immediately prior to ovulation for approximately two hours 3, 5–7 . This period corresponds to ovulation and early corpus luteum (CL) formation in the mouse.…”