Upregulation of the renin-angiotensin system and increased vasoconstrictive response to angiotensin II (AngII) are observed during hypertension in pregnancy (HTN-Preg) and preeclampsia. Although the renin- angiotensin system is upregulated during normal pregnancy (Norm-Preg), reduction in blood pressure (BP) and blunted vascular contraction to AngII are often observed, and the vascular mechanisms involved are unclear. AngII activates angiotensin type 1 receptor (AT1R) to induce vasoconstriction, and angiotensin type 2 receptor (AT2R) to induce the release of vasodilator substances and promote vascular relaxation. The objective of this proposal is to test the hypothesis that AT2R-mediated signaling is an important regulator of vascular function and BP during pregnancy. During Norm-Preg, upregulation of vascular AT2R leads to enhanced vascular relaxation, blunting of vasoconstriction, and reduction in BP. Decreased expression/activity of AT2R-mediated signaling plays a role in the endothelial cell dysfunction and vasoconstriction associated with HTN-Preg, and consequently, increasing the activity of the AT2R system promotes vasodilation and decreases BP in HTN-Preg. Studies will be performed on virgin, Norm-Preg Sprague-Dawley rats and a rat model of HTN-Preg produced by reduction in uterine perfusion pressure (RUPP) during late pregnancy. Ex vivo and molecular studies will be performed on isolated renal and mesenteric arteries and pressurized microvessels.
Aim 1 will determine whether the decreased BP and increased vasodilation during Norm-Preg reflects upregulation of vascular AT2R and postreceptor vascular relaxation pathways. Vascular contraction/relaxation to AngII and phenylephrine will be measured in the absence and presence of AT2R agonists and AT1R antagonists. Vascular AT2R will be quantified using RT-PCR, western blot analysis, and radiolabeled AT receptor binding studies, and localized using immunohistochemistry. Expression of vascular NOS and COX, and the AT2R-induced bradykinin release, nitrite/nitrate and PGI2 production, and membrane potential will be measured.
Aim 2 will determine whether decreased expression/activity of AT2R-mediated signaling plays a role in the endothelial cell dysfunction and enhanced vasoconstriction associated with HTN-Preg. Experiments will test whether AT2R blockade by chronically infusing AT2R antagonist in Norm-Preg rats results in decreased vascular relaxation, and increased vasoconstriction and BP. We will also test whether AT2R-mediated signaling and vascular relaxation pathways are downregulated in RUPP rat model of HTN-Preg. Also, we will test whether enhancing the activity of the AT2R system promotes vasodilation and reduces BP in HTN-Preg. These studies should help to define better the role of vascular AT2R in enhancing vascular relaxation and reducing BP during Norm-Preg. The results will also provide a better understanding of the changes in the vascular AT2R system in the pathogenesis of HTN-Preg and preeclampsia.
Although the role of angiotensin Type 1 receptor (AT1R) in vascular contraction is well-characterized, the role of angiotensin Type 2 receptor (AT2R) in vascular relaxation, particularly during pregnancy, is less clear. The objective of this grant proposal is to test the hypothesis that AT2R-mediated signaling is an important regulator of vascular function and BP during normal pregnancy. Decreased expression/activity of AT2R- mediated signaling pathways plays a role in the endothelial cell dysfunction and vasoconstriction associated with hypertension in pregnancy, and consequently, increasing the activity of the AT2R system promotes vasodilation and decreases BP in hypertension in pregnancy and preeclampsia.
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