Placental hypoxia plays an important role in preeclampsia, a severe form of pregnancy-induced hypertension that afflicts ~5-8% of pregnant women. Preeclampsia has long been associated with thrombotic complications that can be life-threatening. To date, the mechanism that connects placental hypoxia and preeclampsia-associated thrombotic disorders remains poorly understood. Our latest studies indicate that placental hypoxia may up-regulate high mobility group box-1 (HMGB1) protein expression in trophoblasts, which in turn causes endothelial damage and enhances blood coagulation, thereby contributing to thrombosis. In this proposal, we plan to conduct studies to define the role of HMGB1 from hypoxic trophoblasts in preeclampsia-associated thrombotic disease.
In Aim 1, we plan to determine the role of HMGB1 from hypoxic trophoblasts in promoting endothelial microparticle production and blood coagulation in cell- and protein-based studies.
In Aim 2, we plan to examine the role of HMGB1 in promoting endothelial microparticle production and blood coagulation in mouse models. Our studies should help to understand how hypoxia-induced changes in trophoblasts lead to maternal endothelial dysfunction and enhanced blood coagulation in patients with preeclampsia.
Pregnancy-associated thrombotic disorders are major health problems that may lead to life-threatening consequences. To date, the cause of these diseases remains unclear. In our laboratory, we found that placental hypoxia, insufficient blood flow to the placenta, may induce abnormal protein expression that enhances blood clotting and causes thrombosis. In this study, we plan to conduct experiments in cell culture and mouse models of pregnancy-induced hypertension to understand how proteins from hypoxic placental cells activate blood coagulation. Our study may help to develop new ways to reduce the risk of thrombotic disorders in pregnancy.
