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.