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（由申请人提供）：在妊娠高血压（HTN-PREG）和前偏球期间观察到对血管紧张素II（AngII）的血管收缩反应的上调和增加的血管收缩反应。尽管经常观察到正常怀孕期间的肾上腺素 - 血管紧张素系统上调（NORM-PREG），但经常观察到血压（BP）降低（BP）和钝化的血管收缩，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（AT1R）以诱导血管收缩，而血管紧张素2受体（AT2R）诱导血管扩张物质的释放并促进血管松弛。该提案的目的是检验以下假设：AT2R介导的信号传导是怀孕期间血管功能和BP的重要调节剂。在标准preg期间，血管AT2R的上调导致血管松弛，血管收缩的钝化和BP的减少。 AT2R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，增加了AT2R系统的活性会促进血管舒张并降低HTN-PREG中的BP。研究将对初生，标准preg sprague-dawley大鼠进行研究，并在怀孕后期的子宫灌注压力（RUPP）中产生的HTN-PREG大鼠模型。离体和分子研究将在分离的肾脏和肠系膜动脉以及加压的微血管上进行。 AIM 1将确定在标准preg期间的BP减少和血管舒张的增加是否反映了血管AT2R和后受体后血管弛豫途径的上调。在不存在和存在AT2R激动剂和AT1R拮抗剂的情况下，将测量对ANGII和苯肾上腺素的血管收缩/松弛。血管AT2R将使用RT-PCR，Western印迹分析进行定量，并在受体结合研究中进行放射性标记，并使用免疫组织化学定位。血管NOS和COX的表达，以及AT2R诱导的心动激素释放，亚硝酸盐/硝酸盐和PGI2产生以及膜电位。 AIM 2将确定AT​​2R介导的信号传导的表达/活性降低是否在内皮细胞功能障碍和与HTN-PREG相关的血管收缩增强中起作用。实验将测试Norm-Preg大鼠中长期注入AT2R拮抗剂的AT2R阻断是否会导致血管松弛减少，并增加血管收缩和BP。我们还将测试AT2R介导的信号传导和血管松弛途径是否在HTN-PREG的Rupp大鼠模型中下调。另外，我们将测试增强AT2R系统的活性是否促进血管舒张并减少HTN-PREG中的BP。这些研究应有助于更好地定义血管AT2R在增强血管松弛和降低标准preg中BP的作用。结果还将更好地理解HTN-PREG和先兆子痫的发病机理中血管AT2R系统的变化。 公共卫生相关性：尽管血管紧张素1型受体（AT1R）在血管收缩中的作用是充分表征的，但血管紧张素2受体（AT2R）在血管松弛中的作用，尤其是在怀孕期间，尚不清楚。该赠款提案的目的是检验以下假设：AT2R介导的信号传导是正常妊娠期间血管功能和BP的重要调节剂。 AT2R介导的信号通路的表达/活性降低在内皮细胞功能障碍和与妊娠高血压相关的血管收缩中起作用，因此，增加了AT2R系统的活性会促进血管舒张，并促进血管舒张，并降低怀孕和前妇女症患者高血压的BP。