Abstract
Aims: Peroxisome proliferator-activated receptor gamma (PPAR gamma) agonists reduce blood pressure and vascular injury in hypertensive rodents. Pparg 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 Pparg gene in VSMC (smPparg(-/-)) would exaggerate ET-1-induced vascular injury.
Methods and results: eET-1, smPparg(-/-) and eET-1/smPparg(-/-) mice were treated with tamoxifen for 5 days and studied 4 weeks later. SBP was higher in eET-1 and unaffected by smPparg inactivation. Mesenteric artery vasodilatory responses to acetylcholine were impaired only in smPparg(-/-). N-omega -Nitro-L-arginine methyl ester abrogated relaxation responses, and the Ednra/Ednrb mRNA ratio was decreased in eET-1/smPparg(-/-), 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/smPparg(-/-). Mesenteric artery reactive oxygen species increased in smPparg(-/-) and were further enhanced in eET-1/smPparg(-/-). Perivascular fat monocyte/macrophage infiltration was higher in eET-1 and smPparg(-/-) and increased further in eET-1/smPparg(-/-). Spleen CD11b(+) cells were increased in smPparg(-/-) and further enhanced in eET-1/smPparg(-/-), whereas Ly-6C(hi) monocytes increased in eET-1 and smPparg(-/-) but not in eET-1/smPparg(-/-). Spleen T regulatory lymphocytes increased in smPparg(-/-) and decreased in eET-1, and decreased further in eET-1/smPparg(-/-).
Conclusion: VSMC Pparg inactivation exaggerates ET-1-induced vascular injury, supporting a protective role for PPARg in hypertension through modulation of pro-oxidant and proinflammatory pathways. Paradoxically, ET-1 overexpression preserved endothelial function in smPparg(-/-) mice, presumably by enhancing nitric oxide through stimulation of endothelin type B receptors.