Abstract P035: Endothelin-1 Overexpression Preserves Endothelial Function in Mice with Vascular Smooth Muscle Cell-specific Deletion of Ppar-gamma

Abstract

Objective: Peroxisome proliferator-activated receptor γ (PPARγ) agonists reduce blood pressure (BP) and vascular injury in hypertensive rodents and humans. Pparγ inactivation in vascular smooth muscle cells (VSMC)using a tamoxifen inducible Cre-Lox system enhanced angiotensin II-induced vascular injury. Transgenic mice overexpressing endothelin (ET)-1selectively in the endothelium (eET-1) exhibit endothelial dysfunction, increased oxidative stress and inflammation. We hypothesized that inactivation of Pparγ in VSMC(smPparγ-/-)will exaggerate ET-1-induced vascular damage. Methods and Results: Elevenweek-old male control, eET-1, smPparγ-/-and eET-1/smPparγ-/- mice weretreated with tamoxifen (1 mg/kg/day, s.c.) for 5 days and sacrificed 4 weeks later. Systolic BP was higher in eET-1compared to control (123±5 vs 109±2 mmHg,P<0.05)and unaffected by Pparγ inactivation.Mesenteric artery (MA) vasodilatory responses to acetylcholine were impaired only in smPparγ-/- (P<0.05) compared to control (Emax: 52.0±6.7% vs 82.2±4.9%).Reactive oxygen species levels were increased in eET-1, smPparγ-/-and eET-1/smPparγ-/-compared to control (1.7±0.2, 2.2±0.2 and 2.8±0.4 vs 1.0±0.2, P<0.05).MA monocyte chemoattractant protein-1 expression was higher in smPparγ-/-compared to control (31.0±4.4 vs 18.7±2.5, P<0.05), and unaffected by ET-1 overexpression.Perivascular fat monocyte/macrophage infiltration was higher in eET-1 and smPparγ-/- compared to control (331±34 and 326±49 vs 140±8 cells/mm2, P<0.05), and further increased in eET-1/smPparγ-/- (557±77, P<0.05). Nitric oxide synthase (Nos)3 mRNA expression was increased only in eET-1 compared to WT (1.21±0.07 vs 1.00±0.02, P<0.05). Nos2 expression was increased in eET-1 and smPparγ-/-compared to WT (3.69±0.72 and 1.96±0.16 vs 1.00±0.13, P<0.05). The Ednra/EdnrbmRNA ratio was decreased in eET-1/smPparγ-/- compared to smPparγ-/-(0.76±0.04 vs 1.07±0.10, P<0.05). Conclusion: Increased ET-1 paradoxically preserves endothelial function in mice with smPparγinactivation, despite enhancedoxidative stress and inflammation.