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

血管平滑肌细胞（VSMC）的生长受到一种平衡的调节 在增殖和抗增殖因子之间。血管紧张素-（1-7） [Ang-（1-7）]抑制VSMC生长并减少新生内膜形成 血管损伤后。血管生长的减少 肌氨酸可抑制Ang-（1-7）对VSMC的抑制作用 血管紧张素II（Ang II）拮抗剂，但不通过AT 1或AT 2受体 对手。这表明，Ang-2的抗增殖作用， (1-7)是由一种新的非AT 1、非AT 2受体AT（1-7）介导的 受体的我们推测Ang-（1-7）通过抑制血管生长， 前列环素的产生，cAMP的产生增加， cAMP介导的细胞应答的激活。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 血管紧张素-（1-7）抑制血管平滑肌细胞生长的机制， 受体介导血管紧张素-（1-7）的作用。在 具体目标1，前列环素对调节 血管系统中血管紧张素-（1-7）促进血管平滑肌细胞生长。具体目标1： 前列环素对血管紧张素-（1- 7)将被检查，花生四烯酸的不同代谢物的作用， 酸在Ang II和Ang-（1-7）的反调节作用中的作用 将评价血管生长。在具体目标2中， cAMP和cAMP介导的反应在血管生长抑制 将测定Ang-（1-7）。在特异性目标3中，受体激活 血管紧张素-（1-7）在血管平滑肌细胞中的作用， 将通过表达克隆鉴定cDNA。RT-PCR分析将 用于确定AT（1-7）受体是否在血管中发生改变， 来自高血压大鼠（自发性高血压大鼠或 （mRen 2）27只转基因大鼠）或在喂食低盐饮食的大鼠中， 项目1、2和3中所述的研究。的结果予以 研究将确定受体和信号通路 由Ang-（1-7）激活，以反调节 血管紧张素Ⅱ和评估的贡献AT（1-7）受体的作用， 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。

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.