AIMS: Peroxisome proliferator-activated receptor gamma (PPARgamma) agonists reduce blood pressure and vascular injury in hypertensive rodents. Ppargamma 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 Ppargamma gene in VSMC (smPpargamma) would exaggerate ET-1-induced vascular injury. METHODS AND RESULTS: eET-1, smPpargamma and eET-1/smPpargamma mice were treated with tamoxifen for 5 days and studied 4 weeks later. SBP was higher in eET-1 and unaffected by smPpargamma inactivation. Mesenteric artery vasodilatory responses to acetylcholine were impaired only in smPpargamma. N-Nitro-L-arginine methyl ester abrogated relaxation responses, and the Ednra/Ednrb mRNA ratio was decreased in eET-1/smPpargamma, 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/smPpargamma. Mesenteric artery reactive oxygen species increased in smPpargamma and were further enhanced in eET-1/smPpargamma. Perivascular fat monocyte/macrophage infiltration was higher in eET-1 and smPpargamma and increased further in eET-1/smPpargamma. Spleen CD11b cells were increased in smPpargamma and further enhanced in eET-1/smPpargamma, whereas Ly-6C monocytes increased in eET-1 and smPpargamma but not in eET-1/smPpargamma. Spleen T regulatory lymphocytes increased in smPpargamma and decreased in eET-1, and decreased further in eET-1/smPpargamma. CONCLUSION: VSMC Ppargamma inactivation exaggerates ET-1-induced vascular injury, supporting a protective role for PPARgamma in hypertension through modulation of pro-oxidant and proinflammatory pathways. Paradoxically, ET-1 overexpression preserved endothelial function in smPpargamma mice, presumably by enhancing nitric oxide through stimulation of endothelin type B receptors.
- Idris-Khodja, N.
- Ouerd, S.
- Trindade, M.
- Gornitsky, J.
- Rehman, A.
- Barhoumi, T.
- Offermanns, S.
- Gonzalez, F. J.
- Neves, M. F.
- Paradis, P.
- Schiffrin, E. L.