Abstract 343: 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 remodeling and endothelial dysfunction. 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 Ppar gene in VSMC (sm Pparγ -/- ) will exaggerate ET-1-induced vascular damage. Methods: Eleven week-old male control, eET-1, sm Pparγ -/- and eET-1/sm Pparγ -/- mice were used. BP by telemetry, mesenteric artery (MA) reactivity and structure by pressurized myography, reactive oxygen species (ROS) by dihydroethidium (DHE) staining and fibronectin expression by immunofluorescence were determined. Results: Systolic BP was higher in eET-1 and eET-1/sm Pparγ -/- compared to control and sm Pparγ -/- (127±3 and 124±7 vs 109±2 and 114 ± 4 mmHg, respectively, P <0.05). Endothelium-dependent relaxation (EDR) responses to acetylcholine were impaired in sm Pparγ -/- ( P <0.05) but not in eET-1 and sm Pparγ -/- /eET-1 compared with control (E max : 52.0±6.7%, 66.2±7.6 and 87.1±4.4% vs 82.2±4.9%). Endothelium-independent relaxation responses to the nitric oxide donor, sodium nitroprusside, were similar in the four groups. Media/lumen at 45 mmHg was higher only in eET-1/sm Pparγ -/- compared with control (5.5±0.21 vs 4.5±0.21, P <0.05). Increased stiffness was observed in eET-1, sm Pparγ -/- and eET-1/sm Pparγ -/- compared to control, as indicated by a leftward displacement of the stress-strain curves (strain at 140 mmHg: 0.82±0.03, 0.81±0.04, 0.80±0.03 vs 0.97±0.02, P <0.05). ROS levels were increased 1.7±0.2 fold in eET-1, 2.2±0.2 fold in sm Pparγ -/- and 2.8±0.4 fold in eET-1/sm Pparγ -/- compared with control ( P <0.05). Fibronectin staining in MA was similar in the four groups. Conclusion: These results suggest that increased ET-1 paradoxically preserves endothelial function in mice with inactivated Pparγ in vascular smooth muscle, despite presence of enhanced oxidative stress.