Antiproliferative actions of angiotensin-(1-7) in vascular smooth muscle

Hemodynamic factors, circulating hormones, paracrine factors, and intracrin e factors influence vascular smooth muscle growth and plasticity. The well- characterized role of angiotensin II in the modulation of vascular tone and cell function may be critically involved in the mechanisms by which vascul ar smooth muscle responds to signals associated with vascular endothelial d ysfunction and increases in oxidative stress. Studies from this laboratory suggest that the trophic actions of angiotensin II may be intrinsically reg ulated by angiotensin-(1-7), a separate product of the angiotensin system d erived from the common substrate, angiotensin I. Exposure of cultured vascu lar smooth muscle cells to angiotensin-(1-7) inhibited the trophic actions of angiotensin II and reduced the expression of the mitogenic effects of bo th normal serum and platelet-derived growth factor. The growth-inhibitory a ctions of angiotensin-! 1-7) were blocked by the selective D-alanine(7)-ang iotensin-(1-7) antagonist and the nonselective angiotensin receptor blocker sarcosine(1)-threonine(8)-angiotensin II. In contrast, subtype-selective a ntagonists for the AT(1) and AT(2) receptors had no effect on the inhibitor y actions of angiotensin-(1-7), a finding that is consistent with the pharm acological characterization of a high-affinity I-125-labeled angiotensin-(1 -7) binding site in the vasculature by use of selective and nonselective an giotensin II receptor antagonists. The relevance of these findings to the p roliferative response of vascular smooth muscle cells after endothelial inj ury was confirmed by assessment of the effect of a 12-day infusion of angio tensin-(1-7) on neointimal formation. In these experiments, the proliferati ve response produced by injuring the carotid artery was inhibited by angiot ensin-(1-7) through a mechanism that could not be explained by changes in a rterial pressure. Because plasma angiotensin-(1-7) increased to levels comp arable to those found in animals and human subjects given therapeutic doses of angiotensin-converting enzyme inhibitors, angiotensin-(1-7) may be one factor participating in the reversal of vascular proliferation during inhib ition of angiotensin II formation or activity.