Placental development depends on the regulated production of proteolytic enzymes such as plasmin, a key enzyme in the fibrinolytic system. This system plays a critical role in extracellular matrix degradation to facilitate trophoblast invasion of the maternal uterus. Of particular importance in the regulation of plasmin production is the urokinase-type plasminogen activator that is synthesized by trophoblasts and is activated on association with specific receptors, urokinase-type plasminogen activator receptors, located on the surface of trophoblasts. We used an in vitro Matrigel invasion assay to show that Ang II-induced synthesis and secretion of PAI-1 in response to AT1 receptor activation resulted in reduced trophoblast invasion.17 A significant stimulation of PAI-1 secretion from human trophoblasts was also observed with IgG from patients with preeclampsia.11 IgG obtained from normotensive pregnant patients did not stimulate PAI-1 secretion. Activation of AT1 receptors by AT1-AA was blocked by losartan, the 7 amino epitope peptide, and FK506, a calcineurin-specific inhibitor,45 suggesting that calcineurin signaling functions downstream of AT1 receptor activation to mediate PAI-1 induction (Figure 2). Thus, activation of AT1 receptors by AT1-AA on human trophoblasts may contribute to increased PAI-1 production and shallow trophoblast invasion. |