Abstract P223: Caveolin-1 Contributes to Vascular Remodeling and Inflammation Induced by Angiotensin Ii in vivo and in vitro

Abstract

We have recently reported that caveolin-1 (Cav1) enriched membrane microdomains in vascular smooth muscle cells (VSMC) mediate a metalloprotease ADAM17-dependent EGF receptor (EGFR) transactivation, which is linked to vascular remodeling but not contraction induced by angiotensin II (AngII). We have tested our hypothesis that Cav1, a major structural protein of caveolae, plays a critical role for development of vascular remodeling but not hypertension induced by AngII. 8 week old male Cav1-/- and the control Cav+/+ wild-type mice (WT: C57BL6) were infused with AngII (1 μg/kg/min) for 2 weeks to induce vascular remodeling and hypertension. Upon AngII infusion, histological assessments demonstrated medial hypertrophy and perivascular fibrosis of coronary and renal arteries in WT mice compared with sham-operated control mice. The AngII-infused WT mice also showed a phenotype of cardiac hypertrophy with increased heart weight/body weight (HW/BW) ratio (mg/g: 8.0±0.6 vs 5.7±0.7 p<0.01) compared with WT control. In contrast to AngII-infused WT mice, Cav1-/- mice with AngII infusion showed attenuation of vascular remodeling but not cardiac hypertrophy; HW/BW ratio (8.6±0.5 vs 6.4±0.2 p<0.05). Similar levels of AngII-induced hypertension were observed in both WT and Cav1-/- mice assessed by telemetry (mean arterial pressure: 142±9 vs 154±20 mmHg). In WT mice, Ang II enhanced ADAM17 expression and phospho-Tyr1068 EGFR staining in vasculatures of heart and kidney. These events were attenuated in vessels from Cav1-/- mice infused with AngII. In addition, immuno-histochemical analyses revealed less ER stress in heart and kidney of AngII-infused Cav1-/- mice compared with WT mice. Enhanced Cav1 and VCAM-1 expression were also observed in aorta from AngII-infused WT mice but not in Cav1-/- aorta. In rat VSMCs, adenoviral encoding Cav1 siRNA (100 moi) attenuated AngII-induced enhancements of total cell protein, cell volume and extracellular collagen content but not mitochondrial ROS generation. These data suggest that Cav1 and presumably vascular caveolae play critical roles for vascular remodeling and inflammation which likely involves the ADAM17/EGFR cascade independent from blood pressure or mitochondrial ROS regulation.