Complement Activation in Pregnancy and Hypertension

妊娠和高血压中的补体激活

• 批准号: 8574333
• 负责人: JEAN F. REGAL
• 金额: $ 43.72万
• 依托单位: UNIVERSITY OF MINNESOTA DULUTH
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-08-01 至 2015-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8574333
• 关键词: ABT-627; Affect; Angiogenic Factor; Angiotensin II; Angiotensin II Type 1 Receptor Blockers; Animal Model; Antigen-Antibody Complex; Atrasentan; Attenuated; Autoantibodies; Binding; Blood Pressure; C5a anaphylatoxin receptor; Cessation of life; Characteristics; Child; Clinical; Complement; Complement 3a; Complement 5a; Complement Activation; Complement Inactivators; Complement Membrane Attack Complex; Couples; Cultured Cells; Endothelial Cells; Endothelin A Receptor; Endothelin-1; Event; Fetal Growth Retardation; Figs - dietary; Generations; Goals; Habitual Abortion; Health; Host Defense; Human; Hypertension; Hypertension induced by pregnancy; Immune response; In Vitro; Inflammation; Ischemia; Kidney; Link; Losartan; Measures; Mediator of activation protein; Messenger RNA; Mission; Modeling; Mothers; Pathway interactions; Perfusion; Placenta; Plasma; Plasma Proteins; Play; Pre-Eclampsia; Pregnancy; Pregnancy Complications; Premature Birth; Premature Labor; Preproendothelin; Production; Proteinuria; Public Health; Rattus; Reactive Oxygen Species; Receptor Inhibition; Receptor, Angiotensin, Type 1; Research; Role; Syndrome; System; Therapeutic; Third Pregnancy Trimester; United States; United States National Institutes of Health; Vascular Endothelial Growth Factor Receptor-1; Vascular Endothelial Growth Factors; Woman; activation product; adverse outcome; complement system; fetal; in vivo; innovation; neutrophil; novel; pregnancy disorder; pregnancy hypertension; pregnant; pressure; prevent; public health relevance; receptor; trophoblast; vasoconstriction

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.

描述（由申请人提供）：了解怀孕期间胎盘缺血如何导致孕产妇的高血压和唯一有效的治疗是有根本的差距。先兆子痫的研究集中在高血压介质上，包括对血管紧张素II型受体（AT1-AA）和抗血管生成因子（例如可溶性FMS类样酪氨酸激酶-1）的自身抗体，尽管许多女性都不会增加任何女性。最近，我们证明了补体激活与胎盘缺血引起的高血压之间的机械联系，而与降低的血管内皮生长因子无关。然而，尚未研究补体激活与已知的缺血性高血压的已知介体（AT1-AA，内皮素1（ET-1）和活性氧（ROS））之间的机械联系怀孕期间高血压的补体系统激活。长期目标：确定操纵补体系统的治疗效用，以最大程度地减少子痫前期的产妇和胎儿后果。当前建议的总体目标是确定补体激活的机制和导致高血压的临界补体激活产物，以及补体激活与ET-1和ROS途径的关系。这些研究将在大鼠中使用降低的子宫腔灌注压力（RUPP）模型，该模型在三个月中产生胎盘缺血，从而导致高血压和胎儿生长限制，先兆子痫I人的特征。我们针对胎盘缺血事件事件的中心假设是，AT1-AA加血管紧张素II型1型受体（AT1R）的免疫复合物激活了补体，导致活化产物C3A和/或C5A的产生，它们调用ET-1和ROS途径最终导致高血压。具体目标1：确定对补体激活和高血压重要的AT1R，并确定胎盘缺血后对高血压重要的补体激活产物。体内研究将评估AT1R阻滞和C3A/C5A受体拮抗剂对补体激活，ROS，ET-1和高血压的影响。具体目标2：在补体系统激活后，确定内皮素A受体在胎盘缺血引起的高血压中很重要。体内研究以确定补体抑制或内皮素A受体抑制后ROS和ET-1是否增加。用胎盘外植体和培养细胞进行体外研究，以确定补体是否直接刺激ROS和ET-1。这项研究具有创新性，因为它融合了补体系统和妊娠诱发的高血压的基本专业知识，以研究将补体系统激活与已知胎盘缺血诱导的高血压的介体联系起来的新型机械途径。这项贡献将是重要的，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对妊娠诱导的高血压的已知贡献。