Plasminogen activator (PA) deficient mice reveal that plasmin is abundant in the ovary prior to ovulation and required for efficient physiological ovulation

Abstract

Several lines of indirect evidence suggest that plasminogen activators (PAs) plays a crucial role in degradation of the follicular wall during ovulation However, single deficient mice lacking tissue-type PA (tPA), urokinase-type PA (uPA) or PA-inhibitor type 1 (PAI-I) gene function were recently found to have normal reproduction although mice with a combined deficiency of tPA and uPA were significantly less fertile. To investigate whether the reduced fertility of mice lacking PA gene function is due to a reduced ovulation mechanism we have determined the ovulation efficiency, in 25-day old mice By counting the number of oocytes released after gonadotropin-induced ovulation we can thereby quantitate the effect of PA deficiency in a normal physiological process Our results reveal that ovulation efficiency is normal in mice with a single deficiency of tPA or uPA but reduced by 26% in mice lacking both physiological PAs. To dissect the mechanisms behind the reduced ovulation in PA deficient mice, we have studied the regulation of plasmin activity in the ovary. Our data reveal that plasmin activity is regulated throughout the periovulatory period and reaches the highest level prior to ovulation. The plasmin activity were found to be similar in wild-type mice and mice lacking either tPA or PAI-1. while uPA deficient mice had 10% or less of the plasmin activity Since the ovulation efficiency is normal in uPA deficient mice out data indicates that the amount of plasmin generated prior to ovulation in wild-type mice greatly exceeds the amounts required for efficient ovulation. Our data imply that PAs play a role in ovulatory response, although neither tPA nor uPA are obligatory for ovulation. Taken together there seem to be a functionally redundant mechanism for plasmin formation that operates during ovulation where PAs together with other proteases generate the proteolytic activity required for follicular wall degradation.