ANGIOTENSIN-(1-7) AND REGULATION OF VASCULAR GROWTH

血管紧张素-(1-7) 和血管生长的调节

• 批准号: 6573082
• 负责人: Ann Ann Tallant
• 金额: $ 13.19万
• 依托单位: WAKE FOREST UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-04-01 至 2003-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6573082
• 关键词: angiotensin /renin /aldosterone hypertension; angiotensin receptor; angiotensins; cell growth regulation; cell proliferation; cyclic AMP; eicosanoids; genetically modified animals; growth inhibitors; laboratory rat; low salt diet; nitric oxide; nutrition related tag; polymerase chain reaction; receptor expression; renin angiotensin system; spontaneous hypertensive rat; vascular smooth muscle

Vascular smooth muscle cell (VSMC) growth is regulated by a balance between proliferative and anti-proliferative factors. Angiotensin-(1-7) [Ang-(1-7)] inhibits VSMC growth and reduces neointimal formation following vascular injury. The reduction in vascular growth in response to treatment of VSMC with Ang-(1-7) was prevented by the sarcosine antagonists of Angiotensin II (Ang II) but not by AT1 or AT2 receptor antagonists. This suggests that the anti-proliferative effects of Ang- (1-7) are mediated by a novel non-AT1, non-AT2 receptor, the AT(1-7) receptor. We hypothesize that Ang-(1-7) inhibits vascular growth by the production of prostacyclin, an increased in cAMP production and the activation of cAMP-mediated cellular responses. Further, the anti- proliferative effects of Ang-(1-7) are mediated by the AT(1-7) receptor. Thus, the goals of this project of this project are to determine the mechanisms by which Ang-(1-7) inhibits VSMC growth and define the receptor mediating the effects of Ang-(1-7) in the vasculature. In Specific Aim 1, the contribution of prostacyclin to the regulation of VSMC growth by Ang-(1-7) in the vasculature. In Specific Aim 1, the contribution of prostacyclin to the regulation of VSMC growth by Ang-(1- 7) will be examined and the role of distinct metabolites of arachidonic acid in the counter-regulatory effects of Ang II and Ang-(1-7) on vascular growth will be evaluated. In Specific Aim 2, the participation of cAMP and cAMP-mediated responses in vascular growth inhibition by Ang-(1-7) will be determined. In Specific Aim 3, the receptor activated by Ang-(1-7) in VSMC will be pharmacologically characterized and its cDNA will be identified by expression cloning. RT-PCR analyses will be used to determine whether the AT(1-7) receptor is altered in vascular tissues from hypertensive rats (both spontaneous hypertensive rats or (mRen2)27 transgenic rats) or in rats fed a low salt diet, in parallel to studies described in Projects 1, 2 and 3. The results of these studies will identify the receptor and the signaling pathway(s) activated by Ang-(1-7) to counter-regulate the proliferative effects of Ang II and evaluate the contribution of the AT(1-7) receptor to the regulation of arterial pressure in hypertensive animals and during activation of the renin-angiotensin system by low salt.

血管平滑肌细胞 (VSMC) 的生长受平衡调节 增殖因子和抗增殖因子之间。血管紧张素-(1-7) [Ang-(1-7)] 抑制 VSMC 生长并减少新内膜形成 血管损伤后。反应中血管生长减少 肌氨酸阻止了用 Ang-(1-7) 治疗 VSMC 血管紧张素 II (Ang II) 拮抗剂，但不受 AT1 或 AT2 受体拮抗剂的影响 对手。这表明 Ang- 的抗增殖作用 (1-7) 由一种新型非 AT1、非 AT2 受体 AT(1-7) 介导 受体。我们假设 Ang-(1-7) 通过以下方式抑制血管生长： 前列环素的产生，cAMP 产生的增加以及 激活 cAMP 介导的细胞反应。此外，反 Ang-(1-7) 的增殖作用由 AT(1-7) 受体介导。 因此，本项目的目标是确定 Ang-(1-7) 抑制 VSMC 生长的机制并定义 介导血管系统中 Ang-(1-7) 作用的受体。在 具体目标1，前列环素对调节的贡献 VSMC 在血管系统中通过 Ang-(1-7) 生长。在具体目标 1 中， 前列环素对 Ang-(1- 7) 将检查花生四烯酸不同代谢物的作用 Ang II 和 Ang-(1-7) 的反调节作用中的酸 将评估血管生长。在具体目标 2 中，参与 cAMP 和 cAMP 介导的血管生长抑制反应 将测定Ang-(1-7)。在特定目标 3 中，受体被激活 VSMC 中 Ang-(1-7) 的药理学特征及其 cDNA将通过表达克隆来鉴定。 RT-PCR 分析将 用于确定 AT(1-7) 受体在血管中是否发生改变 高血压大鼠的组织（自发性高血压大鼠或 (mRen2)27 转基因大鼠) 或喂食低盐饮食的大鼠，平行 项目 1、2 和 3 中描述的研究。这些结果 研究将确定受体和信号通路 由 Ang-(1-7) 激活以反调节增殖作用 Ang II 并评估 AT(1-7) 受体对 高血压动物和期间动脉压的调节 低盐激活肾素-血管紧张素系统。