Vascular hypertrophy and increased P70S6 kinase in mice lacking the angiotensin II AT2 receptor

Abstract

Background - Angiotensin II activates 2 distinct G protein-coupled receptors, the AT1 and AT2 receptors. Most of the known cardiovascular effects of angiotensin II are mediated by the AT1 receptor subtype. The aim of the present study was to test whether deletion of the AT2 receptor gene in mice (AT2-KO mice) leads to long-term functional or structural alterations in the cardiovascular system. Methods and Results - In vivo pressure responses to angiotensin II or the α1-adrenergic receptor agonist phenylephrine were greatly enhanced in AT2-KO mice. Deletion of the angiotensin AT2 receptor did not lead to a compensatory increase of the activity of the circulating renin-angiotensin system, and arterial blood pressure was identical in wild-type control mice (WT) and AT2-KO mice. Cardiac contractility as assessed by LV catheterization and by rapid MRI also did not differ between AT2-KO and WT mice. Isolated femoral arteries from AT2-KO mice, however, showed enhanced vasoconstriction to angiotensin II, norepinephrine, and K+ depolarization compared with WT. Morphometric analysis of large and small femoral arteries revealed a significant hypertrophy of media smooth muscle cells. Phospho-P70S6 kinase levels were significantly increased in aortas from AT2-KO mice compared with WT mice. Treatment of mice with an ACE inhibitor for 8 weeks abolished the increased pressure responsiveness, vascular hypertrophy, and enhanced P70S6 kinase phosphorylation in AT2-KO mice. Conclusions - These results indicate that vascular AT2 receptors inhibit the activity and, hence, hypertrophic signaling by the P70S6 kinase in vivo and thus are important regulators of vascular structure and function.