Angiotensin II sensitivity, vascular dysfunction and prior preeclampsia

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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.