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.
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