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 a 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. Endothelin-2 (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.

Figure 1.. Synthesis and release of endothelin (EDN).

EDN mRNA is translated into the preproEDN form located in the endoplasmic reticulum, where the N-terminal signal sequence is cleaved by a signal peptidase into proEDN. The proEDN is transferred to Golgi body and cleaved into bigEDN by a proprotein convertase. The bigEDN is then encapsulated by secretory vesicles where it is cleaved into a bioactive form by endothelin converting enzyme (ECE) that is located on the membranes of secretory vesicles. As secretory vesicles fuse with the plasma membrane, EDN is released to the extracellular space. Although each EDN isoform is translated into early proteins of different sizes, all three follow the same synthesis process and become 21-amino acid peptides in their bioactive form.

Figure 2.. Endothelial cell-derived endothelins regulate vascular contractility.

The binding of EDN1 or END2 to EDNRA located in smooth muscle cells (myofibril cells) triggers contraction causing vasoconstriction. Conversely, the binding of EDN1 or END2 to EDNRB located in the endothelial cells induces nitric oxide (NO) production, which triggers smooth muscle cells to relax (vasodilation).

Figure 3.. EDN2 triggers contraction of mature follicles in the ovary.

Prior to follicular rupture, a follicle rapidly grows without support of an accompanying vascular oxygen supply. Granulosa cells of mature preovulatory follicles experiences hypoxia, triggering EDN2 expression. As the follicle grows, proteinases secreted by granulosa cells, theca cells and leukocytes weaken the follicular wall. EDN2 triggers the theca externa that is made of contractile myofibroblast cells to contract, leading to a rupture of the follicle at the apex from which the oocyte is released. EDN2 may bind to EDNRB on vascular endothelial cells and induce nitric oxide (NO) production, thereby causing vasodilation and increasing the vascular permeability; this change may influence follicular rupture but is likely unnecessary for a successful ovulation.