Endothelin 2: a key player in ovulation and fertility

Abstract

Ovulation is the fundamental biological process during which an oocyte is expelled from the ovary, and it is an essential step toward establishing pregnancy. Understanding regulatory mechanisms governing the ovulation process is essential for diagnosing and treating causes of infertility, identifying contraceptive targets, and developing novel contraception methods. EDN2 is a 21-amino acid long peptide that is transiently synthesized by granulosa cells of the ovulatory follicle prior to ovulation and plays an essential role in ovulation via promoting contraction in the myofibroblast cells of the theca layer of the follicle. This review describes the organization of the endothelin system, summarizes recent findings on the expression and synthesis of the endothelin system in the ovary, illustrates the roles that EDN2 plays in regulating ovulation, and discusses EDN2 as a potential target of contraception.

Luteinizing hormone stimulates ingression of mural granulosa cells within the mouse preovulatory follicle

“…The LH-induced ingression of the LH receptor-expressing granulosa cells into the inner half of the mural layer, and the associated changes in cell shape, raised the question of how these cellular events might correlate with LH-induced changes in the shape of the follicle as a whole. Constrictions in the basolateral surface of follicles have been previously observed during or within 2 hours of ovulation, but reports at earlier time points are lacking [24–29]. By fixing ovaries before or 6-10 hours after injection of mice with kisspeptin, labelling the basal lamina in ovary cryosections, and imaging equatorial cross-sections of preovulatory follicles, we observed that invaginations of the follicle surface began much earlier than previously reported.…”

“…Likewise, migration of granulosa cells out of the apical region of the mural granulosa could be imagined to contribute to thinning of the follicle apex. While previous studies have provided evidence for the combined action of extracellular proteases [13,21,27] and endothelin-induced contractions of smooth muscle cells in the theca [29] and theca blood vessels [21] in causing both basolateral invaginations and apical thinning, definitive identification of the cells that are responsible remains uncertain.…”

“…The early changes in follicular shape reported here precede the synthesis of endothelin mRNA by the granulosa cells, which is first detected at 11 hours after injection of mice with the LHR agonist hCG (Palanisamy et al, 2006), corresponding to ~1 hour before ovulation (Figure 1B). Therefore, endothelin-induced constriction of the follicle mediated by contraction of smooth muscle cells in the theca (Ko et al, 2006;Ko et al, 2022) cannot account for these early changes in follicular shape. The extension of LHR-expressing cells into the basolateral follicle wall could be one of the contributing factors.…”

“…Mice with genetically modified cofilin or other cytoskeletal proteins in their granulosa cells could be used to investigate the cytoskeletal mechanisms that mediate LH-induced granulosa cell ingression in preovulatory follicles, and the consequences for follicular shape changes and ovulation. Acting together with contractile events occurring outside of the basal lamina (Ko et al, 2006;Ko et al, 2022;Migone et al, 2016), LH-induced ingression of LHR-expressing cells within the mural granulosa layer is a new component in the complex sequence of structural changes in the follicle that lead to ovulation.…”

“…CC-BY-NC-ND 4.0 International license available under a was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. Ko et al, 2022;Palanisamy et al, 2006). However, granulosa-specific deletion of endothelin-2 in mice only partially inhibits ovulation (Cacioppo et al, 2017), indicating that additional factors may contribute to the follicular constriction.…”