Angiotensin II sensitivity, vascular dysfunction and prior preeclampsia

血管紧张素 II 敏感性、血管功能障碍和先兆子痫

• 批准号: 8916215
• 负责人: Ellen W Seely
• 金额: $ 62.95万
• 依托单位: BRIGHAM AND WOMEN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-09-15 至 2017-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8916215
• 关键词: Acute; Adrenal Glands; Aldosterone; Angiotensin II; Angiotensin Receptor; Antibodies; Blood Pressure; Blood Vessels; Cardiovascular Diseases; Cells; Clinical; Clinical Trials; Data; Development; Diet; Dietary Sodium; Disease; Endothelium; Equilibrium; Excretory function; Future; Goals; Health; Hypertension; Immunoglobulin G; In Vitro; Individual; Infusion procedures; Intake; Intervention; Intravenous; Kidney; Lead; Measurement; Measures; Mediating; Mediator of activation protein; Peripheral Blood Mononuclear Cell; Pilot Projects; Plasma; Population; Pre-Eclampsia; Pregnancy; Premenopause; Proteins; Receptor Activation; Receptor, Angiotensin, Type 1; Recording of previous events; Relative (related person); Renal Blood Flow; Risk; Risk Factors; Sodium; Sodium Chloride; Staging; Testing; Vascular Diseases; Vascular Endothelial Growth Factor Receptor-1; Vascular Endothelial Growth Factors; Vasodilation; Woman; base; cardiovascular disorder risk; cardiovascular risk factor; human study; in vivo; insight; normotensive; novel; prevent; receptor; receptor sensitivity; renal artery; response; urinary; vasoconstriction

DESCRIPTION (provided by applicant): A history of preeclampsia is a risk factor for cardiovascular disease (CVD), but the mechanism mediating the increased CVD risk is unknown. Our preliminary results have demonstrated increased angiotensin II (Ang II) sensitivity and salt sensitivity of blood pressure in women with prior hypertensive pregnancy. Thus, this proposal hypothesizes that Ang II sensitivity is mediated by Ang II Type 1 Receptor (AT1R) Activation which Is a Key Mechanistic Factor Leading to Both Vascular Dysfunction and Salt Sensitivity of Blood Pressure, Leading to Future Development of Hypertension and Increased CVD Risk in Women with a History of Preeclampsia. We will test this hypothesis through the following three specific aims: 1) To test the hypothesis that in women with a history of preeclampsia, AT1R activation is associated with vascular dysfunction manifesting as increased Ang II pressor sensitivity and impaired endothelial dependent vasodilation and that AT1R blockade corrects the vascular dysfunction; 2) To test the hypothesis that women with a history of preeclampsia have excess AT1R activity in the kidney leading to impaired ability to augment renal blood flow in response to dietary sodium and in the adrenal leading to increased aldosterone secretion (both correctable by AT1R blockade) and impaired ability to excrete a sodium load, all of which lead to salt sensitivity of blood pressure; 3) To test the hypothesis tha the increased AT1R activity will be explained by alterations in AT1R and/or AT2R level or responsiveness as determined in peripheral blood mononuclear cells obtained from women studied in SAs 1-2. Women with a history of preeclampsia will be studied 1-5 years after pregnancy and compared to women with prior normotensive pregnancy. This proposal will provide insight into the mechanism by which women with a history of preeclampsia are at increased risk for hypertension and CVD, and importantly will set the stage for a clinical trial of blockade of the AT1R to prevent future CVD in women with a history of preeclampsia.

描述（由申请人提供）：先兆子痫病史是心血管疾病（CVD）的危险因素，但介导 CVD 风险增加的机制尚不清楚。我们的初步结果表明，妊娠期高血压妇女的血压血管紧张素 II (Ang II) 敏感性和盐敏感性增加。因此，该提议假设Ang II敏感性是由Ang II 1型受体（AT1R）激活介导的，这是导致血管功能障碍和血压盐敏感性的关键机制因素，导致未来高血压的发展和CVD风险增加有先兆子痫病史的女性。我们将通过以下三个具体目标来检验这一假设：1）检验以下假设：在有先兆子痫病史的女性中，AT1R 激活与血管功能障碍相关，表现为 Ang II 升压敏感性增加和内皮依赖性血管舒张受损，并且 AT1R 阻断纠正血管功能障碍； 2) 检验以下假设：有先兆子痫病史的女性肾脏中 AT1R 活性过高，导致对膳食钠的反应而增加肾血流量的能力受损，而肾上腺中则导致醛固酮分泌增加（两者均可通过 AT1R 阻断来纠正）排钠能力受损，所有这些都会导致血压对盐敏感； 3) 检验以下假设：AT1R 活性增加可以通过 AT1R 和/或 AT2R 水平或反应性的改变来解释，如在 SA 1-2 中研究的女性外周血单核细胞中测定的。有先兆子痫病史的女性将在怀孕后 1-5 年接受研究，并与之前妊娠时血压正常的女性进行比较。该提案将深入了解有先兆子痫病史的女性患高血压和心血管疾病的风险增加的机制，重要的是将为以下临床试验奠定基础： 阻断 AT1R 可预防有先兆子痫病史的女性未来发生 CVD。