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Endothelin-2 – role in ovarian follicle rupture
Ovulation occurs at around day 14 of the human menstrual cycle and refers to the release of an egg, characterised by the rupture of a preovulatory ovarian follicle. This process is driven changes in oestrogen-regulated feedback on the HPG axis, leading to a surge of LH which drives follicular rupture. There is a complex molecular dialogue for ovulation which involves the coordinated expression of many key proteins, including Endothelin 2 (ET-2).

Within the follicle ET-2 expression is confined to the granulosa cells, where its production peaks transiently at the final stages before ovulation (periovulatory stage). In the mouse, there is a surge of E2 around two hours prior to ovulation, this is thought to act as one of the driving forces for follicular rupture. Much of our current understanding of ET-2 and its role during ovulation comes from rodent model experiments. However, there are some interspecies discrepancies, with stark differences identified between the mouse and bovine ovary.

The mechanisms underlying ET-2-induced follicle rupture are debated, with most theories suggesting a mechanical contraction pathway. ET-2 is believed to act on the follicle by stimulating the endothelin receptor A (EDNRA), which is expressed constitutively on the external layer of theca cells, causing smooth muscle cells surrounding the ovary to contract. This smooth muscle layer encapsulates the ovary but is absent at the site of oocyte expulsion, creating a region of low surface tension which weakens the follicle wall and promotes the release of an egg.

ET-2 also binds to and activates the endothelin B receptor (EDNRB), which is constitutively expressed by granulosa cells and theca interna. There is controversy surrounding the role of ET-2 signalling at this receptor. Some studies suggest that EDNRB activation by ET-2 regulates follicular rupture by antagonising effects of EDNRA stimulation. Alternatively, EDNRB may propel follicular rupture by inducing nitric oxide signalling. This results in local vasodilation, contributing to the rise in follicular fluid pressure seen in the periovulatory phase.