There is a fundamental gap in understanding how placental ischemia during pregnancy leads to maternal hypertension and the only effective cure is early delivery of placenta. Studies of preeclampsia have focused on many mediators of hypertension including endothelin (ET-1) and reactive oxygen species (ROS). We recently demonstrated a mechanistic link between complement activation, specifically C3a and C5a, and placental ischemia-induced hypertension. However, the cause of complement activation and the mechanistic link between complement activation and known mediators of placental ischemia-induced hypertension, ET-1 and ROS, have not been investigated and are critically needed to identify the exact role of complement activation in hypertension during pregnancy. Long term goal: Determine therapeutic utility of manipulating complement system to minimize maternal and fetal consequences of preeclampsia. Overall objective: Identify mechanisms upstream and downstream of complement activation that lead to placental ischemia-induced hypertension. The central hypothesis for events following placental ischemia is that complement is activated by interaction of newly exposed antigens or neoantigens such as ?2-glycoprotein I (?2-GPI) with natural IgM antibody leading to complement activation and generation of C3a and C5a subsequently invoking ET-1 and ROS pathways to ultimately result in endothelial dysfunction and hypertension. In addition, we hypothesize that placental ischemia affects complement regulators that normally control the degree of complement activation. These studies will use reduced uteroplacental perfusion pressure (RUPP) model in rat that produces placental ischemia in third trimester resulting in endothelial dysfunction, hypertension and fetal growth restriction, characteristics of preeclampsia in humans. Specific Aim 1: Identify the mechanism of increased complement activation after placental ischemia. In vivo studies will assess effect of blocking ?2-GPI binding on neoantigen, IgM and complement deposition, complement activation products C3a/C5a, complement regulators, ROS, ET-1, endothelial dysfunction and hypertension. Specific Aim 2: Identify endothelin A receptor as important in placental ischemia-induced endothelial dysfunction and hypertension following complement system activation. In vivo studies will determine if ROS and ET-1 increase after inhibiting complement activation, and if ROS, ET-1 and complement activation increase after endothelin A receptor inhibition. In vitro studies with placental explants and cultured cells will determine if complement products directly stimulate ROS and ET-1. This research is innovative as it couples essential expertise in neoantigens, natural antibody and complement with pregnancy-induced hypertension to investigate novel mechanistic pathways. This contribution will be significant because it will define the cause of complement activation following placental ischemia and determine if therapy targeted at complement activation or its cause is feasible or if dual therapy to impact multiple mediator systems is required to manage hypertension in pregnancy.
NIH ExPorter
NIH ExPorter