A coordinated and cell-specific induction of both physiological plasminogen activators create redundant mechanisms for plasmin formation during ovulation in the mouse

Abstract

The plasminogen activator (PA)-system togelher with matrix metalloprotcinases (MMPs) arc thought to play a crucial role in the degradation of (he follicle wall during ovulation. In keeping with this the ovulation efficiency is reduced with 26% in mice deficient for both urokinase-typc plasminogcn activator (uPA) and tissue-type plasminogen activator (tPA) compared to wild-type mice. Surprisingly, the ovulation efficiency is normal in single deficient mice, lacking either tPA or uPA gene function, although most of the plasmin activity induced prior to ovulation is caused by uPA. This results indicate that PAs play a role in ovulation but that neither tPA nor uPA is obligatory for ovulation. The loss of an individual PA also appears to be functionally compensated by the remaining PA. To further characterize the role of the PA-system during ovulation induction we have used in situ hybridization and in situ zymography to localize the cellular sites of PAs and PA-inhibitors mRNA synthesis and to determine the distribution of tPA and uPA activity in the mouse ovary. Our data reveals that although uPA is the major PA synthesized in the ovary during gonadotropin induced ovulation there is a coordinated induction of tPA at the surface of the ovary at 4 h after hCG treatment. This tPA activity may be responsible for the plasmin production which causes normal ovulation in uPA deficient mice. Only low levels of PAI-1 and PAI-2 mRNAs were detected in the ovary. However, the more broad-spectrum proteasc inhibitor, protease nexin-1, were expressed at high levels during the whole pcriovulatory period indicating that this inhibitor may play a role in the mouse ovary.