Abstract 14133: Angiotensin II-induced Vascular Fibrosis was Prevented by Caveolin-1 Deficient Mice
Introduction: We have recently reported that caveolin-1 (Cav1) enriched membrane microdomains in vascular smooth muscle cells (VSMC) mediates a metalloprotease ADAM17-dependent EGF receptor (EGFR) transactivation, which is linked to vascular remodeling induced by AngII.
Hypothesis: We have tested our hypothesis that Cav1, a major structural protein of caveolae, plays a critical role in AngII-mediated vascular remodeling via regulation of ADAM17 and EGFR.
Methods: In vivo: 8 week old male Cav1-/- and control Cav+/+ wild-type mice (WT) were infused with AngII (1 μg/kg/min) for 2 weeks to induce vascular remodeling and hypertension.
In vitro: Rat aortic VSMCs were cultured and stimulated with 100 nM AngII.
Results: Upon AngII infusion, histological assessments demonstrated medial hypertrophy and perivascular fibrosis of coronary and renal arteries in WT mice compared to sham-operated mice. The AngII-infused WT mice also showed a phenotype of cardiac hypertrophy with increased HW/BW ratio (mg/g: 8.0±0.6 vs 5.7±0.7 p<0.01) compared with sham-operated WT control. In contrast, vascular remodeling but not cardiac hypertrophy were attenuated in Cav1-/- mice with AngII infusion; HW/BW ratio (8.6±0.5 vs 6.4±0.2 p<0.05) compared to sham-operated mice. However, AngII induced similar levels of hypertension in both WT and Cav1-/- mice as assessed by telemetry (MAP mmHg: 142±9 vs 154±20). AngII infusion in WT mice enhanced ADAM17 and phospho-Tyr EGFR staining in heart and kidney vasculature, whereas AngII-infused Cav1-/- mice showed diminished ADAM17 and phospho-Tyr EGFR staining within the vasculature. In addition, IHC analyses revealed reduced vascular ER stress in heart and kidney samples of AngII-infused Cav1-/- mice compared to WT mice. In cultured rat VSMC, Cav1 silencing attenuated induction and activation of ADAM17 by AngII.
Conclusions: These data suggest that Cav1, and presumably caveolae microdomains, plays a critical role in vascular fibrosis via vascular induction of ADAM17 and activation of EGFR independent of blood pressure or cardiac hypertrophy regulation.
Author Disclosures: T. Kawai: None. S.J. Forrester: None. K.J. Elliot: None. S. Eguchi: None. V. Rizzo: None.
- © 2015 by American Heart Association, Inc.