Role of Angiotensin II and Chronic Inflammation in Persistent Microvascular Dysfunction Following Preeclamptic Pregnancy

项目总结/摘要 在怀孕期间发生先兆子痫的其他健康女性在怀孕期间发生先兆子痫的风险显著增加（2-4倍）。 心血管疾病（CVD）发病率和死亡率的风险更高;然而， 这种关联尚不清楚。一个新的假设是这种关联是长期升高 炎症和不可逆的内皮损伤持续在先兆子痫怀孕期间， 产后为了支持这一假设，有先兆子痫病史的健康女性表现出升高的 炎症细胞因子，以及血管收缩剂对血管紧张素II（ang II）的敏感性增加和减弱 内皮依赖性血管舒张。此外，来自啮齿动物模型的令人信服的数据表明， 血管紧张素II和炎症介质之间的信号传导导致严重的血管功能障碍， 先兆子痫怀孕总之，这些数据表明，血管紧张素II和炎症的慢性变化， 信号传导可能导致促收缩环境，其中内皮依赖性血管舒张减弱， 降低的一氧化氮生物利用度和过度的血管收缩导致持续的血管功能障碍， 患有先兆子痫的女性。然而，很少有体内研究试图研究这些， 人类的机制。使用一种创新的翻译人类方法，结合1）体内药理学， 解剖血管功能障碍的机制，2）免疫细胞活性的体外测量，和3）两者 急性和慢性药物治疗，拟议研究的总体目标是 异常血管紧张素II信号传导和慢性炎症的综合机制检查-包括新的 干预途径-在其他健康的妇女谁有先兆子痫。 在具体目标1中，我们将定义血管紧张素II信号在微血管炎症中的机制作用， 与对照组相比， 有一个健康的怀孕。在具体目标2中，我们将定义 血管紧张素1-7（血管紧张素II信号传导的内源性抑制剂）。在具体目标3中，我们将确定 全身性Ang II 1型受体抑制（长期口服氯沙坦治疗）对体内和体外测量 炎症和内皮功能。这一全面评估 介导持续性微血管功能障碍的机制，以及通过 它可以减轻这种功能障碍，直接将细胞和动物的功能和分子发现转化为 研究的临床人群，并将提供深入了解慢性心血管疾病风险升高的管理， 患有先兆子痫的女性。这些项目将扩大申请人的综合培训 通过让她获得新的技术技能，包括体外生化分析， 人外周血单核细胞，同时提供强有力的指导培训， 专业发展，为PI过渡到独立而量身定制。

Project Summary/Abstract Otherwise healthy women who develop preeclampsia during pregnancy are at a significantly (2-4 times) greater risk for cardiovascular disease (CVD) morbidity and mortality; however, the mechanism(s) responsible for this association remain unclear. One emerging hypothesis for this association is chronically elevated inflammation and irreversible endothelial damage sustained during the preeclamptic pregnancy that persist postpartum. In support of this hypothesis, healthy women with a history of preeclampsia demonstrate elevated inflammatory cytokines, as well as increased vasoconstrictor sensitivity to angiotensin II (ang II) and attenuated endothelium-dependent vasodilation. Further, compelling data from rodent models suggest that potentiated signaling between ang II and inflammatory mediators contribute to severe vessel dysfunction during a preeclamptic pregnancy. Taken together, these data suggest that chronic changes in ang II and inflammatory signaling may lead to a pro-constrictor milieu in which attenuated endothelium-dependent vasodilation, reduced nitric oxide bioavailability, and exaggerated vasoconstriction result in persistent vessel dysfunction in women who have had preeclampsia. However, few, if any, in vivo studies have sought to investigate these mechanisms in humans. Using an innovative translational human approach that combines 1) in vivo pharmaco- dissection of mechanisms of vascular dysfunction, 2) in vitro measures of immune cell activity, and 3) both acute and chronic pharmacological treatments, the overarching goal of the proposed studies is a comprehensive mechanistic examination of aberrant ang II signaling and chronic inflammation - including novel interventional pathways - in otherwise healthy women who have had preeclampsia. In specific aim 1 we will define the mechanistic role of ang II signaling in microvascular inflammation and associated endothelial dysfunction in women who have had preeclampsia compared to control women who have had a healthy pregnancy. In specific aim 2 we will define the mechanistic anti-inflammatory role of angiotensin 1-7 (an endogenous inhibitor of ang II signaling). In specific aim 3 we will determine the effect of systemic ang II type 1 receptor inhibition (chronic oral losartan therapy) on in vivo and in vitro measures of inflammation and endothelial function in women who have had preeclampsia. This comprehensive assessment of mechanisms mediating persistent microvascular dysfunction, and the identification of novel mechanisms by which to mitigate this dysfunction, directly translates functional and molecular findings of cell and animal studies to a clinical population and will lend insight into the management of chronic elevated CVD risk in women who have had preeclampsia. These projects will extend the applicant’s training in integrative cardiovascular physiology by allowing her to acquire new technical skills, including in vitro biochemical analysis of human peripheral blood mononuclear cells, while simultaneously providing strong mentored training and professional development, tailored to transition the PI to independence.