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 the placenta. Studies of preeclampsia have focused on mediators of hypertension including autoantibodies to angiotensin II type I receptor (AT1-AA) and anti-angiogenic factors such as soluble fms-like tyrosine kinase-1 despite the observation that many women do not present with increases in either. We have recently demonstrated a mechanistic link between complement activation and placental ischemia-induced hypertension independent of decreased vascular endothelial growth factor. However, a mechanistic link between complement activation and known mediators of placental ischemia-induced hypertension [AT1-AA, endothelin 1 (ET-1) and reactive oxygen species (ROS)] has NOT been investigated and is critically needed to identify the exact role of complement system 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 of the current proposal is to determine the mechanism of complement activation and the critical complement activation product(s) leading to hypertension, as well as the relationship of complement activation to ET-1 and ROS pathways. These studies will use reduced uteroplacental perfusion pressure (RUPP) model in rat that produces placental ischemia in third trimester resulting in hypertension and fetal growth restriction, characteristics of preeclampsia i humans. Our central hypothesis for events following placental ischemia is that complement is activated by immune complexes of AT1-AA plus angiotensin II type 1 receptor (AT1R) leading to generation of activation products C3a and/or C5a, which invoke ET-1 and ROS pathways to ultimately contribute to hypertension.
Specific Aim 1 : Identify the AT1R as important for complement activation and hypertension and identify complement activation products important for hypertension following placental ischemia. In vivo studies will assess effect of AT1R blockade and C3a/C5a receptor antagonists on complement activation, ROS, ET-1 and hypertension.
Specific Aim 2 : Identify endothelin A receptor as important in placental ischemia-induced hypertension following complement system activation. In vivo studies to determine if ROS and ET-1 increase after complement inhibition or endothelin A receptor inhibition. In vitro studies with placental explants and cultured cells to determine if complement products directly stimulate ROS and ET-1. This research is innovative because it couples essential expertise in complement system and pregnancy- induced hypertension to investigate novel mechanistic pathways linking complement system activation to known mediators of placental ischemia-induced hypertension. This contribution will be significant because it will determine if therapy targeted at the cause of complement activation or specific complement activation products (C3a, C5a) will impact the known contribution of ET-1 or ROS to pregnancy-induced hypertension.

Public Health Relevance

The proposed research is relevant to public health because preeclampsia and related hypertensive disorders of pregnancy affect ~10% of all pregnancies in the United States, significantly impacting the health of both mother and child. Preeclampsia is a leading cause of maternal death (18%) and premature birth (15%). The project is relevant to the mission of NIH because mechanistic studies linking complement system activation to other mediator systems important in hypertension and intrauterine growth restriction will determine the potential therapeutic benefit of manipulating the complement system to manage and/or prevent the hypertension of preeclampsia and potentially minimize adverse consequences for both mother and child.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Academic Research Enhancement Awards (AREA) (R15)
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Special Emphasis Panel (ZRG1-VH-C (90))
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Mitchell, Megan S
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University of Minnesota Duluth
Anatomy/Cell Biology
Schools of Medicine
United States
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