Complement activation and angiogenic imbalance in pregnancy and hypertension

描述（由申请人提供）：在了解妊娠期胎盘缺血如何导致母亲高血压和儿童宫内生长受限（IUGR）方面存在根本差距。在妊娠期高血压的研究中，研究的重点是促血管生成因子（血管内皮生长因子）和抗血管生成因子（可溶性纤维样酪氨酸激酶-1，可溶性内啡肽）导致高血压的平衡。在补体系统与妊娠的研究中，研究重点是免疫介导事件中血管生成失衡导致胎儿丢失。提出的研究测试补体系统和胎盘缺血后高血压之间的关键机制联系。长期目标：确定操纵补体系统的治疗效用，以防止先兆子痫或减少产妇/胎儿的后果。本研究的总体目标是确定补体激活是大鼠子宫胎盘灌注压降低（RUPP）模型中导致母体/胎儿不良后果的关键事件，该模型与子痫前期高血压密切相关。妊娠晚期大鼠胎盘缺血模型表现为血管生成失衡、内皮功能障碍、高血压和IUGR；人类先兆子痫的所有特征。胎盘缺血后事件的中心假设是补体激活导致补体裂解产物C5a的产生和胎盘中性粒细胞浸润，导致血管生成失衡、内皮功能障碍、高血压和IUGR。特异性目标#1：确定补体激活和C5a的产生是胎盘中性粒细胞浸润、血管生成失衡和由此导致的内皮功能障碍、高血压和胎盘缺血引起的IUGR的关键事件。体内研究将评估补体激活并确定抑制补体激活和拮抗C5a受体的作用。胎盘外植体、滋养细胞和炎症细胞的体外研究将确定补体激活是直接改变胎盘血管生成平衡还是需要炎症细胞浸润。特异性目的2：确定胎盘中性粒细胞浸润是导致胎盘缺血引起的血管生成失衡以及由此导致的内皮功能障碍、高血压和IUGR的关键事件。体内研究将评估中性粒细胞耗竭的影响。这项拟议的研究具有创新性，因为它将补体系统和炎症的基本专业知识与妊娠高血压的动物模型相结合，以研究导致血管生成失衡并导致母亲和儿童不良后果的新机制途径。这些研究将确定补体系统激活和中性粒细胞积累在复杂妊娠中引起高血压和IUGR的重要性。这一贡献将是重要的，因为它将确定补体系统或中性粒细胞积累的操作是否是预防和/或治疗子痫前期高血压的可行治疗选择。

DESCRIPTION (provided by applicant): There is a fundamental gap in understanding how placental ischemia during pregnancy leads to hypertension in the mother and intrauterine growth restriction (IUGR) of the child. In studies of hypertension in pregnancy, the research focus is on the balance of pro-angiogenic factors (vascular endothelial growth factor) and anti-angiogenic factors (soluble fms-like tyrosine kinase-1, soluble endoglin) leading to hypertension. In studies of complement system and pregnancy the research focus is on angiogenic imbalance leading to fetal loss in immune mediated events. The proposed studies test the critical mechanistic link between complement system and hypertension following placental ischemia. Long term goal: Determine the therapeutic utility of manipulating the complement system to prevent preeclampsia or minimize maternal/fetal consequences. Overall objective of the current proposal is to identify complement activation as a critical event leading to adverse maternal/fetal consequences in the reduced uteroplacental perfusion pressure (RUPP) model in the rat that closely mimics hypertension associated with preeclampsia. This model of placental ischemia in the 3rd trimester pregnant rat is characterized by angiogenic imbalance, endothelial dysfunction, hypertension and IUGR; all characteristics of preeclampsia in humans. The central hypothesis for events following placental ischemia is that complement activation leads to generation of the complement cleavage product C5a and placental neutrophil infiltration resulting in angiogenic imbalance, endothelial dysfunction, hypertension and IUGR. Specific Aim #1: Identify complement activation and generation of C5a as a critical event for placental neutrophil infiltration, angiogenic imbalance and the resultant endothelial dysfunction, hypertension, and IUGR caused by placental ischemia. In vivo studies will assess complement activation and determine the effect of inhibiting complement activation and antagonizing the C5a receptor. In vitro studies with placental explants, trophoblast cells and inflammatory cells will determine if complement activation directly alters angiogenic balance in the placenta or requires infiltration of inflammatory cells. Specific Aim 2: Identify placental neutrophil infiltration as a critical event leading to angiogenic imbalance and the resultant endothelial dysfunction, hypertension, and IUGR caused by placental ischemia. In vivo studies will assess the effect of neutrophil depletion. The proposed research is innovative because it couples essential expertise in the complement system and inflammation with animal models of pregnancy induced hypertension to investigate novel mechanistic pathways that precede angiogenic imbalance and lead to adverse consequences for mother and child. These studies will determine the importance of complement system activation and neutrophil accumulation as a cause of hypertension and IUGR in complicated pregnancies. This contribution will be significant because it will determine if manipulation of the complement system or neutrophil accumulation is a feasible therapeutic option for prevention and/or treatment of hypertension associated with preeclampsia. 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 hypertension and intrauterine growth restriction will determine the potential therapeutic benefit of manipulating the complement system or neutrophil infiltration to treat and/or prevent the hypertension of preeclampsia and potentially minimize adverse consequences for both mother and child.