Abstract
BACKGROUND: Angiotensin II activates 2 distinct G protein-coupled
receptors, the AT(1) and AT(2) receptors. Most of the known cardiovascular
effects of angiotensin II are mediated by the AT(1) receptor subtype.
The aim of the present study was to test whether deletion of the
AT(2) receptor gene in mice (AT(2)-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 alpha(1)-adrenergic
receptor agonist phenylephrine were greatly enhanced in AT(2)-KO
mice. Deletion of the angiotensin AT(2) 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 AT(2)-KO mice. Cardiac contractility as assessed by
LV catheterization and by rapid MRI also did not differ between AT(2)-KO
and WT mice. Isolated femoral arteries from AT(2)-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 AT(2)-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 AT(2)-KO mice. CONCLUSIONS: These results
indicate that vascular AT(2) receptors inhibit the activity and,
hence, hypertrophic signaling by the P70S6 kinase in vivo and thus
are important regulators of vascular structure and function.
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