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Peroxisome proliferator-activated receptor γ (PPARγ) agonists reduce blood pressure and vascular injury in hypertensive rodents. Pparγ inactivation in vascular smooth muscle cells (VSMC) enhances vascular injury. Transgenic mice overexpressing endothelin (ET)-1 selectively in the endothelium (eET-1) exhibit endothelial dysfunction, increased oxidative stress and inflammation. We hypothesized that inactivation of the Pparγ gene in VSMC (smPparγ−/−) would exaggerate ET-1-induced vascular injury.eET-1, smPparγ−/− and eET-1/smPparγ−/− mice were treated with tamoxifen for 5 days and studied 4 weeks later. SBP was higher in eET-1 and unaffected by smPparγ inactivation. Mesenteric artery vasodilatory responses to acetylcholine were impaired only in smPparγ−/−. Nω-Nitro-L-arginine methyl ester abrogated relaxation responses, and the Ednra/Ednrb mRNA ratio was decreased in eET-1/smPparγ−/−, which could indicate that nitric oxide production was enhanced by ET-1 stimulation of endothelin type B receptors. Mesenteric artery media/lumen was greater only in eET-1/smPparγ−/−. Mesenteric artery reactive oxygen species increased in smPparγ−/− and were further enhanced in eET-1/smPparγ−/−. Perivascular fat monocyte/macrophage infiltration was higher in eET-1 and smPparγ−/− and increased further in eET-1/smPparγ−/−. Spleen CD11b+ cells were increased in smPparγ−/− and further enhanced in eET-1/smPparγ−/−, whereas Ly-6Chi monocytes increased in eET-1 and smPparγ−/− but not in eET-1/smPparγ−/−. Spleen T regulatory lymphocytes increased in smPparγ−/− and decreased in eET-1, and decreased further in eET-1/smPparγ−/−.VSMC Pparγ inactivation exaggerates ET-1-induced vascular injury, supporting a protective role for PPARγ in hypertension through modulation of pro-oxidant and proinflammatory pathways. Paradoxically, ET-1 overexpression preserved endothelial function in smPparγ−/− mice, presumably by enhancing nitric oxide through stimulation of endothelin type B receptors.