Prostaglandin E2 Acts via Multiple Receptors to Regulate Plasminogen-Dependent Proteolysis in the Primate Periovulatory Follicle

Abstract

The ovulatory gonadotropin surge regulates expression of plasminogen activator (PA) family members within the ovarian follicle, which are implicated in follicle wall degradation at ovulation. Gonadotropin also stimulates follicular prostaglandin E2 (PGE2) production, which is required for follicle rupture. To determine whether the ovulatory gonadotropin surge regulates PA-mediated proteolysis via PGE2 in the primate follicle, monkeys received gonadotropins to stimulate follicle development. Follicular aspirates or whole ovaries were obtained before (0 h) and after human chorionic gonadotropin (hCG) administration to span the periovulatory interval. Granulosa cell levels of tissue-type PA (tPA) and PA inhibitor type 1 (PAI-1) proteins were low at 0 h hCG and higher after hCG administration. In situ zymography showed no ovarian tPA activity 0 h after hCG; tPA activity was present in granulosa cells obtained after hCG treatment. Importantly, tPA and PAI-1 proteins and tPA activity were low/nondetectable in granulosa cells obtained after treatment with hCG and the PG synthesis inhibitor celecoxib. To determine whether hCG stimulation of tPA and PAI-1 requires PGE2, granulosa cells obtained at 0 h were cultured with hCG plus indomethacin to inhibit PG production; some cells also received PGE2 or an agonist selective for one PGE2 receptor (EP). PGE2, an EP2 agonist, and an EP3 agonist increased tPA protein, whereas PGE2, an EP1 agonist, and an EP3 agonist increased PAI-1 protein. Therefore, gonadotropin increases granulosa cell tPA and PAI-1 protein levels and tPA-dependent proteolytic activity. PGE2 also increases tPA and PAI-1 protein levels in granulosa cells, suggesting that elevated PGE2 late in the periovulatory interval acts to stimulate proteolysis and follicle rupture. Different prostaglandin E2 receptors increase granulosa cell expression of tissue type plasminogen activator (PA) and PA inhibitor type 1, so receptor-selective agonists may be useful to promote or prevent proteolysis needed for ovulation.