Abstract P224: 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. Pparγ inactivation in vascular smooth muscle cells (VSMC) using a tamoxifen inducible Cre-Lox system enhanced angiotensin II-induced vascular damage. Transgenic mice overexpressing endothelin (ET)-1 in the endothelium (eET-1) exhibit endothelial dysfunction, increased oxidative stress and inflammation. We hypothesized that inactivation of the Ppar gene in VSMC (sm Pparγ -/- ) would exaggerate ET-1-induced vascular damage. Methods and Results: Eleven-week-old male control, eET-1, sm Pparγ -/- and eET-1/sm Pparγ -/- mice were treated with tamoxifen (1 mg/kg/day, s.c.) for 5 days and sacrificed 4 weeks later. Systolic BP determined by telemetry was higher in eET-1 (123±5 vs 109±2 mm Hg, P <0.05) and unaffected by sm Pparγ inactivation. Mesenteric artery (MA) vasorelaxation to acetylcholine was impaired only in sm Pparγ -/- (E max : 52.0±6.7 vs 82.2±4.9%, P <0.05). MA reactive oxygen species levels were increased 1.7±0.3-fold in sm Pparγ -/- ( P <0.05) and further increased in eET-1/sm Pparγ -/- (2.5±0.3-fold, P <0.05). MA perivascular fat monocyte/macrophage infiltration was higher in eET-1 and sm Pparγ -/- (331±34 and 326±49 vs 140±8 cells/mm 2 , P <0.05), and further increased in eET-1/sm Pparγ -/- (557±77, P <0.05). The spleen fraction of CD11b + cells was increased in sm Pparγ -/- (1.1±0.1 vs 0.47±0.1%, P <0.05) and further increased in eET-1/sm Pparγ -/- (1.8±0.2%, P <0.05). The spleen fraction of Ly-6C hi monocytes was increased in eET-1 and sm Pparγ -/- (24±3 and 27±4 vs 14±1%, P <0.05) but not in eET-1/sm Pparγ -/- . The spleen fraction of T regulatory cells was increased in sm Pparγ -/- (13±2 vs 9±1%, P <0.05) and decreased in eET-1 (7±1%, P <0.05), which was further decreased by eET-1/sm Pparγ -/- (3±1%, P <0.05). Conclusions: These results suggest that increased ET-1 paradoxically preserves endothelial function in mice with inactivated VSMC Pparγ despite enhanced oxidative stress. Flow cytometry data indicate that infiltrating monocyte/macrophages in these mice might be anti-inflammatory.