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.
aHypertension and Vascular Research Unit, Lady Davis Institute for Medical Research
bDepartment of Medicine, Sir Mortimer B. Davis-Jewish General Hospital, McGill University, Montreal, Quebec, Canada
cDepartment of Clinical Medicine, State University of Rio de Janeiro, Rio de Janeiro, Rio de Janeiro, Brazil
dDepartment of Pharmacology, Max-Planck-Institute for Heart and Lung Research, Bad Nauheim, Germany
eLaboratory of Metabolism, Division of Basic Sciences, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA
*Noureddine Idris-Khodja and Sofiane Ouerd contributed equally to the article.
Correspondence of Ernesto L. Schiffrin, C.M., MD, PhD, FRSC, FRCPC, Department of Medicine, Sir Mortimer B. Davis-Jewish General Hospital, #B-127, 3755 Côte-Ste-Catherine Rd., Montreal, QC, Canada H3T 1E2. Tel: +1 514 340 7538; fax: +1 514 340 7539; e-mail: email@example.com
Abbreviations: Arg-1, arginase-1; ANOVA, analysis of variance; BP, blood pressure; CD206, mannose receptor; CreERT2, tamoxifen-inducible Cre recombinase fused with a modified estrogen receptor ligand-binding domain; DHE, dihydroethidium; eET-1, transgenic mice constitutively overexpressing human ET-1 selectively in the endothelium; eNOS, endothelial nitric oxide synthase; ET, endothelin; ETA, endothelin type A; ETB, endothelin type B; FABP4, fatty acid binding protein 4; FOXP3, forkhead box P3; iNOS, inducible nitric oxide synthase; L-NAME, Nω-nitro-L-arginine methyl ester; MA, mesenteric artery; MCP-1, monocyte chemotactic protein-1; MHC-II, major histocompatibility complex class II; MOMA-2, monocyte/macrophage antigen-2; NE, norepinephrine; NO, nitric oxide; PPARγ, peroxisome proliferator-activated receptor gamma; PVAT, perivascular adipose tissue; ROS, reactive oxygen species; Rps16, ribosomal protein S16; smPparγ−/−, inactivation of the Pparγ gene in VSMC; SNP, sodium nitroprusside; SOD, superoxide dismutase; TL, tibia length; Treg, T-regulatory lymphocytes; VSMC, vascular smooth muscle cells
Received 13 December, 2016
Revised 16 January, 2017
Accepted 6 February, 2017
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