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）：子痫病史是心血管疾病（CVD）的危险因素，但是介导CVD风险增加的机制尚不清楚。我们的初步结果表明，血管紧张素II（ANG II）的敏感性和盐敏感性对先前高血压妊娠的女性的血压敏感性增加。因此，该提案假设ANG II敏感性是由ANG II 1型受体（AT1R）激活介导的，这是导致血压血管功能障碍和盐灵敏度的关键机制因素，从而导致高血压的未来发展和患有前丙酸率史的女性CVD风险增加。我们将通过以下三个特定目的来检验这一假设：1）检验以下假设：在具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施加敏感性和受损的内皮血管舒张性并且AT1R阻断的良好性较高，而AT1R则纠正了AT1R的良好性。 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）为了检验假设，AT1R活性的增加将通过AT1R和/或AT2R水平的改变或反应性来解释，或在外周血血液单核细胞中确定的，从SAS 1-2中研究的妇女获得。具有先兆子痫病史的妇女将在怀孕1 - 5年后与先前怀孕正常的妇女进行研究。该提案将洞悉具有先兆子痫病史的妇女的高血压风险和CVD的风险增加，重要的是，重要的是，将为临床试验奠定基础 封锁AT1R，以防止具有先兆子痫史的妇女的未来CVD。