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(Circulation. 2001;104:2602.)
© 2001 American Heart Association, Inc.

Basic Science Reports

Vascular Hypertrophy and Increased P70S6 Kinase in Mice Lacking the Angiotensin II AT₂ Receptor

Marc Brede; Kerstin Hadamek; Lorenz Meinel; Frank Wiesmann, MD; Jörg Peters, MD; Stefan Engelhardt, MD; Andreas Simm, MD; Axel Haase, PhD; Martin J. Lohse, MD; Lutz Hein, MD

From the Institut für Pharmakologie und Toxikologie (M.B., K.H., L.M., S.E., M.J.L., L.H.), Medizinische Universitätsklinik (F.W.), Physikalisches Institut (F.W., A.H.), and Institut für Klinische Biochemie und Pathobiochemie (A.S.), Universität Würzburg, and the Institut für Pharmakologie, Universität Heidelberg (J.P.), Germany.

Correspondence to Lutz Hein, MD, Institut für Pharmakologie und Toxikologie, Universität Würzburg, Versbacher Strasse 9, 97078 Würzburg, Germany. E-mail hein{at}toxi.uni-wuerzburg.de

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 ₁-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.

Key Words: angiotensin • receptors • hypertrophy • vasculature • magnetic resonance imaging

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