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

血管平滑肌细胞(VSMC)生长受平衡调节 在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生长并减少新生内膜形成 在血管损伤之后。反应中血管生长的减少 肌氨酸预防Ang-(1-7)治疗VSMC 血管紧张素II的拮抗剂，但不是AT1或AT2受体 对抗者。这提示血管紧张素转换酶的抗增殖作用。 (1-7)是由一种新的非AT1、非AT2受体AT(1-7)介导的 受体。我们假设Ang-(1-7)通过抑制血管生长 前列环素的生产，cAMP产量的增加和 激活cAMP介导的细胞反应。此外，反- Ang-(1-7)的促增殖作用是由AT(1-7)受体介导的。 因此，这个项目的目标是确定 血管紧张素-(1-7)抑制VSMC生长及其机制的研究 受体介导Ang-(1-7)在血管系统中的作用在……里面 具体目标1，前列环素在调节血管生成中的作用 血管内皮细胞生长。在具体目标1中， 前列环素在Ang-(1-)调节VSMC生长中的作用 7)将被检测和花生四烯酸不同代谢物的作用 血管紧张素Ⅱ和血管紧张素-(1-7)的反调节作用中的酸 将对血管生长进行评估。在具体目标2中，参与 在血管生长抑制中cAMP和cAMP介导的反应 Ang-(1-7)将被确定。在特定的目标3中，受体被激活 Ang-(1-7)在VSMC中的药理学特征及其 将通过表达克隆的方法对其进行鉴定。RT-PCR分析将是 用于确定血管内AT(1-7)受体是否发生改变 来自高血压大鼠的组织(自发性高血压大鼠或 (MRen2)27只转基因大鼠)或同时饲喂低盐饮食的大鼠 项目1、2和3中描述的研究。这些研究的结果 研究将确定受体和信号通路(S) 血管紧张素-(1-7)激活对血管内皮细胞增殖的抑制作用 Ang II并评价AT(1-7)受体在血管紧张素转换酶中的作用 高血压动物的动脉压调节 低盐激活肾素-血管紧张素系统。

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.