title: Protective role of vascular smooth muscle cell PPARγ in angiotensin II-induced vascular disease.
abstract: OBJECTIVE
  Vascular peroxisome proliferator-activated receptor γ (PPARγ) activation improves vascular remodelling and endothelial function in hypertensive rodents. The goal of this study was to determine that vascular smooth muscle cell (VSMC) PPARγ exerts a vascular protective role beyond its metabolic effects.
  
  
  RESULTS
  We generated a model of adult inducible VSMC-specific Pparγ inactivation to test the hypothesis that PPARγ counteracts angiotensin (Ang) II-induced vascular remodelling and endothelial dysfunction. Inducible VSMC Pparγ knockout mice were generated by crossing Pparγ floxed mice with mice expressing a tamoxifen-inducible Cre recombinase Smooth muscle (Sm) myosin heavy chain promoter control. Eight-to-ten-week-old SmPparγ(-/-) and control mice were infused with a nonpressor dose of Ang II for 7 days. Blood pressure was unaffected. Mesenteric arteries showed eutrophic remodelling in Ang II-infused control mice and hypertrophic remodelling in Ang II-infused SmPparγ(-/-) mice. Endothelium-dependent relaxation to acetylcholine was reduced in SmPparγ(-/-) mice and further impaired by Ang II infusion, and was unaffected by an inhibitor of NO synthase, suggesting a defect of NO-mediated relaxation. SmPparγ deletion increased the sensitivity to Ang II-induced contraction. SmPparγ(-/-) mice exhibited enhanced Ang II-induced vascular NADPH oxidase activity and adhesion molecule ICAM-1 and chemokine monocyte chemotactic protein-1 expression. The antioxidant Superoxide dismutase 3 expression was decreased by SmPparγ deletion. Ang II infusion increased the expression of CD3 T-cell co-receptor chain δ and decreased Adiponectin in perivascular adipose tissue of SmPparγ(-/-) mice.
  
  
  CONCLUSIONS
  Inducible Pparγ inactivation in VSMCs exacerbated Ang II-induced vascular remodelling and endothelial dysfunction via enhanced vascular oxidative stress and inflammation, revealing the protective role of VSMC PPARγ in angiotensin II-induced vascular injury.
authors.affiliation: Lady Davis Institute for Medical Research, Jewish General Hospital, McGill University, Montreal, Quebec,  Canada.
authors.forename: Chiara
authors.initials: C
authors.lastname: Marchesi
authors.forename: Asia
authors.initials: A
authors.lastname: Rehman
authors.forename: Yohann
authors.initials: Y
authors.lastname: Rautureau
authors.forename: Daniel A
authors.initials: DA
authors.lastname: Kasal
authors.forename: Marie
authors.initials: M
authors.lastname: Briet
authors.forename: Avshalom
authors.initials: A
authors.lastname: Leibowitz
authors.forename: Stefania M C
authors.initials: SM
authors.lastname: Simeone
authors.forename: Talin
authors.initials: T
authors.lastname: Ebrahimian
authors.forename: Mario F
authors.initials: MF
authors.lastname: Neves
authors.forename: Stefan
authors.initials: S
authors.lastname: Offermanns
authors.forename: Frank J
authors.initials: FJ
authors.lastname: Gonzalez
authors.forename: Pierre
authors.initials: P
authors.lastname: Paradis
authors.forename: Ernesto L
authors.initials: EL
authors.lastname: Schiffrin
mesh_terms: D000804:Angiotensin II / Q000009:adverse effects*; D000818:Animals; D018932:Chemokine CCL2 / Q000378:metabolism; D004195:Disease Models, Animal; D004730:Endothelium, Vascular / Q000378:metabolism / Q000503:physiopathology; D006973:Hypertension / Q000139:chemically induced / Q000378:metabolism / Q000473:pathology; D018799:Intercellular Adhesion Molecule-1 / Q000378:metabolism; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D009131:Muscle, Smooth, Vascular / Q000166:cytology / Q000378:metabolism*; D009249:NADP / Q000378:metabolism; D018384:Oxidative Stress / Q000502:physiology; D047495:PPAR gamma / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D013482:Superoxide Dismutase / Q000378:metabolism; D014652:Vascular Diseases / Q000139:chemically induced* / Q000378:metabolism* / Q000473:pathology
chemical_list: C491768:Ccl2 protein, mouse; D018932:Chemokine CCL2; D047495:PPAR gamma; D000804:Angiotensin II; D018799:Intercellular Adhesion Molecule-1; D009249:NADP; C499090:Sod3 protein, mouse; D013482:Superoxide Dismutase