HORMONE REGULATION OF THE FIBRINOLYTIC SYSTEM IN THE OVARY

Abstract

In the ovary, the release of oocytes from graafian follicles during hormone-induced ovulation has been found to be associated with substantial increases in follicular plasminogen activator (PA) activity. Most of the PA activity comes from the granulosa cells that have been shown to produce tPA, uPA as well as the type-1 PA-inhibitor,(PAI-1).We have studied the molecular mechanism of follicle stimulating hormone (FSH) and gonadotropin releasing hormone (GnRH) on the synthesis of tPA in primary cultures of rat granulosa cells. FSH and GnRH were both found to induce tPA in granulosa cells in a time and dose dependent manner. The effect of FSH and GnRH on the levels of tPA mRNA was also studied by northern and slot blot hybridizations. FSH and GnRH were both found to increase the level of tPA mRNA. The stimulation was up to 18 -fold compared to untreated cells.The induction of tPA mRNA by FSH and GnRH was additive and the time courses of the stimulation by the hormones differed, suggesting that different cellular mechanisms are involved. Consistent with the ability of FSH to activate the cAMP dependent protein kinase A pathway, the phosphodiesterase inhibitor 1-methyl-3-isobutylxanthine further enhanced the FSH induction of tPA mRNA.GnRH is known to activate the phospholipid-dependent protein kinase C pathway. Likewise the effect of GnRH can be mimicked by the kinase C activator, phorbol myristate acetate.It is concluded that FSH and GnRH regulates tPA production by differnt molecular mechanisms, and that the increase in tPA activity is mediated via an increase in the levels tPA mRNA. Since both gonadotropins and GnRH cause ovulation in hyposectomized animals, similar stimulatory actions of these hormones on the tPA activity suggest a correlative relationship between this enzyme and the ovulatory process.