Angiotensin II sensitivity, vascular dysfunction and prior 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，但调节CVD风险增加的机制尚不清楚。我们的初步结果表明，既往有高血压妊娠史的女性对血管紧张素II(Ang II)的敏感性和对盐的敏感性都有所增加。因此，这一建议假设Ang II敏感性是由Ang II 1型受体(AT1R)激活介导的，AT1R是导致血管功能障碍和血压盐敏感性的关键机制因素，导致高血压的未来发展和有先兆子痫病史的女性心血管疾病风险增加。我们将通过以下三个具体目标来检验这一假说：1)检验这一假说：在有子痫前期病史的妇女中，AT1R激活与血管功能障碍有关，表现为Ang II升压敏感性增加和内皮依赖性血管扩张受损，AT1R阻断可纠正血管功能障碍；2)检验有先兆子痫病史的妇女肾脏AT1R活性过高，导致肾脏AT1R活性过高，导致肾上腺对饮食钠反应增加肾脏血流量的能力受损，导致醛固酮分泌增加(均可通过AT1R阻滞剂纠正)和排泄钠负荷能力受损的假说，所有这些都会导致血压的盐敏；3)为了验证AT1R活性增加将通过AT1R和/或AT2R水平或反应性的变化来解释这一假设，AT1R和/或AT2R水平或从SAS1-2研究对象的外周血单核细胞中检测到的反应性。有先兆子痫病史的妇女将在怀孕1-5年后进行研究，并与既往正常血压妊娠的妇女进行比较。这项建议将深入了解有先兆子痫病史的妇女患高血压和心血管疾病风险增加的机制，重要的是将为临床试验奠定基础。 阻断AT1R以预防有先兆子痫病史的妇女未来的心血管疾病。

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.