Complement Activation in Pregnancy and Hypertension

描述（由申请人提供）：对于妊娠期胎盘缺血如何导致孕妇高血压的理解存在根本性的空白，唯一有效的治疗方法是早期胎盘娩出。先兆子痫的研究主要集中在高血压的介质，包括血管紧张素II型受体（AT1-AA）的自身抗体和抗血管生成因子，如可溶性类膜酪氨酸激酶-1，尽管观察到许多妇女两者均未增加。我们最近证明了补体激活和胎盘缺血诱导的高血压之间的机制联系，而不依赖于血管内皮生长因子的降低。然而，补体激活与胎盘缺血诱导高血压的已知介质[AT1-AA，内皮素1 （ET-1）和活性氧（ROS）]之间的机制联系尚未被研究，并且迫切需要确定补体系统激活在妊娠期高血压中的确切作用。长期目标：确定操纵补体系统的治疗效用，以尽量减少母体和胎儿子痫前期的后果。本研究的总体目标是确定补体激活的机制和导致高血压的关键补体激活产物，以及补体激活与ET-1和ROS途径的关系。这些研究将采用降低子宫胎盘灌注压（RUPP）模型，在妊娠晚期产生胎盘缺血，导致高血压和胎儿生长受限，这是人类子痫前期的特征。我们对胎盘缺血后事件的中心假设是补体被AT1-AA +血管紧张素II型1受体（AT1R）的免疫复合物激活，导致激活产物C3a和/或C5a的产生，激活ET-1和ROS途径最终导致高血压。具体目标1：确定AT1R对补体激活和高血压的重要作用，并确定补体激活产物对胎盘缺血后高血压的重要作用。体内研究将评估AT1R阻断剂和C3a/C5a受体拮抗剂对补体激活、ROS、ET-1和高血压的影响。特异性目的2：确定内皮素A受体在补体系统激活后胎盘缺血诱导高血压中的重要作用。体内研究确定补体抑制或内皮素A受体抑制后ROS和ET-1是否增加。利用胎盘外植体和培养细胞进行体外研究，以确定补体产品是否直接刺激ROS和ET-1。这项研究具有创新性，因为它结合了补体系统和妊娠高血压的基本专业知识，研究了补体系统激活与胎盘缺血诱导高血压已知介质之间的新机制途径。这一贡献将是重要的，因为它将确定针对补体激活原因或特定补体激活产物（C3a, C5a）的治疗是否会影响ET-1或ROS对妊娠高血压的已知贡献。

DESCRIPTION (provided by applicant): 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.