title: Vascular hypertrophy and increased P70S6 kinase in mice lacking the angiotensin II AT(2) receptor.
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.
  
  
  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.
authors.affiliation: Institut für Pharmakologie und Toxikologie, Medizinische Universitätsklinik, Physikalisches Institut , Universität Würzburg, Germany.
authors.forename: M
authors.initials: M
authors.lastname: Brede
authors.forename: K
authors.initials: K
authors.lastname: Hadamek
authors.forename: L
authors.initials: L
authors.lastname: Meinel
authors.forename: F
authors.initials: F
authors.lastname: Wiesmann
authors.forename: J
authors.initials: J
authors.lastname: Peters
authors.forename: S
authors.initials: S
authors.lastname: Engelhardt
authors.forename: A
authors.initials: A
authors.lastname: Simm
authors.forename: A
authors.initials: A
authors.lastname: Haase
authors.forename: M J
authors.initials: MJ
authors.lastname: Lohse
authors.forename: L
authors.initials: L
authors.lastname: Hein
mesh_terms: D000806:Angiotensin-Converting Enzyme Inhibitors / Q000494:pharmacology; D000818:Animals; D001794:Blood Pressure; D002216:Captopril / Q000494:pharmacology; D046508:Culture Techniques; D006321:Heart / Q000503:physiopathology; D006439:Hemodynamics; D006984:Hypertrophy / Q000209:etiology / Q000473:pathology / Q000503:physiopathology; D008279:Magnetic Resonance Imaging; D051379:Mice; D018345:Mice, Knockout; D009213:Myography; D010766:Phosphorylation; D044139:Receptor, Angiotensin, Type 2; D011945:Receptors, Angiotensin / Q000235:genetics* / Q000502:physiology*; D019893:Ribosomal Protein S6 Kinases / Q000378:metabolism*; D015398:Signal Transduction; D014652:Vascular Diseases / Q000209:etiology* / Q000473:pathology / Q000503:physiopathology; D014661:Vasoconstriction
chemical_list: D000806:Angiotensin-Converting Enzyme Inhibitors; D044139:Receptor, Angiotensin, Type 2; D011945:Receptors, Angiotensin; D002216:Captopril; D019893:Ribosomal Protein S6 Kinases