In the last 30 years, remarkable progress has been made in our understanding of the biological role of endothelins in the regulation of reproductive function and fertility. A peptide hormone identified for its ability to regulate blood pressure has now been shown as a potent mediator of several reproductive pathways. Ligand-and receptor-specific roles have been identified and/or postulated during follicular development and ovulation as well as in the function and regression of the corpus luteum. In this review we have attempted to organize endothelin-mediated ovarian processes in a process-specific manner, rather than compile a review of ligand-or isoform-specific actions. Further, we have included a discussion on "post-ovarian" or oviductal function, as well as the future directions that we believe will increase our understanding of endothelin biology as a whole.
KeywordsEndothelin; ovary; oviduct; ovulation; follicle; corpus luteum
INTRODUCTION
ENDOTHELINSEndothelins were first identified in a hallmark paper by Yanigasawa et al. (1) as potent vasoactive peptides, regulating vascular tone and blood pressure. However, diversity in biological function became readily apparent with many other roles for these peptides now described. Three isoforms of endothelins (EDN1, 2 and 3) coded by three different genes (2) have been identified to date (3). These 21 amino acid peptides are derived by cleavage of the biologically inactive "big-endothelin" by the action of at least 2 endothelin converting enzymes (ECE1 and ECE2). The biological effects of endothelin production are then determined via activation of one of two G-protein coupled receptors, endothelin receptors A and B (EDNRA and EDNRB). EDNRA has a high affinity for both EDN1 and EDN2 (and a low affinity for EDN3) whereas EDNRB has a similar affinity for all the isoforms (4).Genetic deletion of components of the endothelin system has highlighted the importance of these peptides rather than defining tissue specific effects. Endothelin-1 knockout mice die of respiratory failure at birth (5), EDN2 knockout mice exhibit growth retardation and juvenile
NIH Public Access
Author ManuscriptFront Biosci (Schol Ed). Author manuscript; available in PMC 2011 January 28.
Published in final edited form as:Front Biosci (Schol Ed). ; 3: 145-155.
NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author Manuscript lethality (6), EDN3 knockout mice exhibit aganglionic megacolon and die young (7), EDNRA knockout mice are embryonic lethal (8) and EDNRB knockout mice die close to the age of puberty (9). Researchers have therefore relied heavily on the use of agonists and antagonists to study the function of these peptides, however conditional transgenic models are now becoming more readily available. As expected from their structure, the three purified peptide ligands are available for commercial purchase, albeit not always in a species-specific state. Similarly, a plethora of antagonists can be purchased, selective (or not) in their antagonism to either EDNRA or EDNRB. W...