Vascular Angiotensin Type-2 Receptor in Normal and Hypertensive Pregnancy

正常妊娠和高血压妊娠中的血管紧张素 2 型受体

• 批准号: 7835652
• 负责人: Raouf A Khalil
• 金额: $ 8.61万
• 依托单位: BRIGHAM AND WOMEN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-05-08 至 2012-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7835652
• 关键词: Address; Agonist; Angiotensin II; Angiotensin II Type 1 Receptor Blockers; Angiotensins; Animals; Aortic Segment; Applications Grants; Blood Pressure; Blood Vessels; Bradykinin; Bradykinin Receptor; Cyclic AMP; Cyclic GMP; Cyclooxygenase Inhibitors; Data; Endothelial Cells; Endothelium; Epoprostenol; Functional disorder; Hypertension; Immunohistochemistry; In Vitro; Kidney; Measurement; Measures; Mediating; Membrane Potentials; Mesenteric Arteries; Modeling; Molecular; Nitrates; Nitrites; Pathogenesis; Pathway interactions; Perfusion; Phenylephrine; Pilot Projects; Play; Potassium Channel; Pre-Eclampsia; Pregnancy; Production; Protein Isoforms; Radiolabeled; Rattus; Receptor, Angiotensin, Type 1; Relaxation; Renin-Angiotensin System; Reverse Transcriptase Polymerase Chain Reaction; Role; Signal Pathway; Signal Transduction; Sprague-Dawley Rats; System; Testing; Tissues; Type 2 Angiotensin II Receptor; United States National Institutes of Health; Up-Regulation; Vasodilation; Vasodilator Agents; Western Blotting; channel blockers; hemodynamics; in vivo; pregnancy hypertension; pressure; public health relevance; radiotracer; receptor; receptor binding; receptor-mediated signaling; renal artery; research study; response; vasoconstriction

DESCRIPTION (provided by applicant): 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. PUBLIC HEALTH RELEVANCE: 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.

描述（由申请方提供）：在妊娠高血压（HTN-Preg）和先兆子痫期间观察到肾素-血管紧张素系统上调和对血管紧张素II（AngII）的血管收缩反应增加。尽管在正常妊娠期间（Norm-Preg），肾素-血管紧张素系统上调，但经常观察到血压（BP）降低和血管收缩减弱至AngII，并且涉及的血管机制尚不清楚。AngII激活血管紧张素1型受体（AT 1 R）诱导血管收缩，激活血管紧张素2型受体（AT 2 R）诱导血管舒张物质释放，促进血管舒张。本提案的目的是检验AT 2 R介导的信号传导是妊娠期间血管功能和血压的重要调节剂这一假设。在Norm-Preg期间，血管AT 2 R的上调导致血管舒张增强、血管收缩减弱和BP降低。AT 2 R介导的信号传导的表达/活性降低在与HTN-Preg相关的内皮细胞功能障碍和血管收缩中起作用，因此，增加AT 2 R系统的活性促进HTN-Preg中的血管舒张并降低BP。研究将在未孕、Norm-Preg Sprague-Dawley大鼠和妊娠晚期子宫灌注压降低（RUPP）产生的HTN-Preg大鼠模型中进行。将对离体肾动脉和肠系膜动脉以及加压微血管进行离体和分子研究。目的1将确定Norm-Preg期间血压降低和血管舒张增加是否反映了血管AT 2 R和受体后血管舒张通路的上调。将在不存在和存在AT 2 R激动剂和AT 1 R拮抗剂的情况下测量血管对AngII和苯肾上腺素的收缩/舒张。将使用RT-PCR、蛋白质印迹分析和放射性标记AT受体结合研究定量血管AT 2 R，并使用免疫组织化学进行定位。将测量血管NOS和考克斯的表达、AT 2 R诱导的缓激肽释放、亚硝酸盐/硝酸盐和PGI 2的产生以及膜电位。目的2将确定AT 2 R介导的信号传导的表达/活性降低是否在与HTN-Preg相关的内皮细胞功能障碍和血管收缩增强中起作用。实验将测试在Norm-Preg大鼠中通过长期输注AT 2 R拮抗剂进行的AT 2 R阻断是否导致血管舒张减少以及血管收缩和BP增加。我们还将测试AT 2 R介导的信号传导和血管舒张通路是否在HTN-Preg的RUPP大鼠模型中下调。此外，我们将测试是否增强AT 2 R系统的活性促进血管舒张和降低血压在HTN-Preg。这些研究有助于更好地确定血管AT 2 R在Norm-Preg期间增强血管舒张和降低BP中的作用。该结果也将提供更好地了解血管AT 2 R系统在HTN-Preg和先兆子痫发病机制中的变化。 公共卫生关系：虽然血管紧张素1型受体（AT 1 R）在血管收缩中的作用已得到充分表征，但血管紧张素2型受体（AT 2 R）在血管舒张中的作用，特别是在妊娠期间，尚不清楚。这项资助提案的目的是检验AT 2 R介导的信号传导是正常妊娠期间血管功能和血压的重要调节剂这一假设。AT 2 R介导的信号传导途径的表达/活性降低在与妊娠高血压相关的内皮细胞功能障碍和血管收缩中起作用，因此，增加AT 2 R系统的活性促进血管舒张并降低妊娠高血压和先兆子痫中的BP。