Vascular smooth muscle cell peroxisome proliferator-activated receptor γ protects against endothelin-1-induced oxidative stress and inflammation

Abstract

Aims: 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. Methods and results: 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 -/-. N ω -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-6C hi 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 -/-. Conclusion: 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.