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

血管紧张素 II 和慢性炎症在先兆子痫妊娠后持续性微血管功能障碍中的作用

基本信息

批准号：
10246810
负责人：
ANNA STANHEWICZ
金额：
$ 24.9万
依托单位：
UNIVERSITY OF IOWA
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-03-03 至 2023-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10246810
关键词：
Acute Affect Angiotensin II Angiotensins Animals Anti-Inflammatory Agents Attenuated Biochemical Biological Availability Blood Circulation Blood Vessels Cardiovascular Diseases Cardiovascular Physiology Cells Chronic Clinical Clinical Management Coupled Cutaneous Data Development Disease remission Dissection Dose Endothelium Fibrosis Functional disorder Goals Human Immune Immune response In Vitro Inflammation Inflammation Mediators Inflammatory Inflammatory Response Infusion procedures Interleukin-6 Intervention Investigation Lead Life Link Losartan Measures Mediating Mentors Microcirculatory Bed Microdialysis Microvascular Dysfunction Molecular Morbidity - disease rate NF-kappa B Nature Nitric Oxide Oral Pathway interactions Peripheral Blood Mononuclear Cell Pharmacological Treatment Pharmacology Physiological Population Postpartum Period Postpartum Women Pre-Eclampsia Pregnancy Prevention strategy Receptor Inhibition Receptor, Angiotensin, Type 1 Recording of previous events Risk Rodent Model Role Signal Transduction Superoxides Symptoms TNF gene Technical Expertise Testing Therapeutic Time Training Translating United States Vascular Diseases Vasoconstrictor Agents Vasodilation Woman cardiovascular disorder risk clinical practice cytokine endothelial dysfunction factor A healthy pregnancy in vivo inhibitor/antagonist innovation insight mortality novel response salicylsalicylic acid targeted treatment treatment strategy vasoconstriction

项目摘要

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.

项目概要/摘要在其他方面健康的女性在怀孕期间发生先兆子痫的风险显着（2-4 倍）心血管疾病（CVD）发病率和死亡率的风险更大；然而，负责的机制对于这种关联尚不清楚。关于这种关联的一个新的假设是长期升高的先兆子痫妊娠期间持续存在的炎症和不可逆的内皮损伤产后。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) 的敏感性增加并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，增强血管紧张素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妊娠。综上所述，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会导致促收缩环境，其中内皮依赖性血管舒张减弱，一氧化氮生物利用度降低和血管过度收缩导致持续性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调查这些人类的机制。使用创新的人类转化方法，结合了 1) 体内药物- 血管功能障碍机制的剖析，2) 免疫细胞活性的体外测量，以及 3) 两者急性和慢性药物治疗，拟议研究的总体目标是对异常的 Ang II 信号传导和慢性炎症进行全面的机制检查 - 包括新的介入途径 - 对于患有先兆子痫的健康女性。在具体目标 1 中，我们将定义 Ang II 信号传导在微血管炎症中的机制作用和与患有先兆子痫的女性相比，患有先兆子痫的女性的相关内皮功能障碍拥有健康的怀孕经历。在具体目标 2 中，我们将定义其抗炎作用的机制血管紧张素 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，我们将确定以下效果：全身性 Ang II 1 型受体抑制（慢性口服氯沙坦治疗）对体内和体外测量的影响患有先兆子痫的女性的炎症和内皮功能。此次综合评估介导持续性微血管功能障碍的机制，以及通过以下方法识别新机制为了减轻这种功能障碍，直接转化细胞和动物的功能和分子发现对临床人群进行研究，并将有助于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。这些项目将扩展申请人的综合培训心血管生理学，让她获得新技术技能，包括体外生化分析人类外周血单核细胞，同时提供强有力的指导培训和专为 PI 过渡到独立而量身定制的专业发展。

项目成果

期刊论文数量（7）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Residual vascular dysfunction in women with a history of preeclampsia.

DOI：
10.1152/ajpregu.00204.2018
发表时间：
2018-12
期刊：
American journal of physiology. Regulatory, integrative and comparative physiology
影响因子：
0
作者：
A. Stanhewicz
通讯作者：
A. Stanhewicz

Women with a history of preeclampsia have preserved sensory nerve-mediated dilatation in the cutaneous microvasculature.