Endothelial cell specific knockout of caveolin-1 attenuates AngII/BAPN-induced vascular remodeling in mice.

Caveolin-1 null mice (Cav1-/-) are protected from developing vascular diseases while mice expressing Cav1 solely in the endothelium are capable of disease progression. To explore potential mechanisms through which endothelial caveolin-1 contribute to vascular disease, we subjected Cav1 fl/fl Cre - and endothelial cell specific, caveolin-1 knockout mice (Cav1 fl/fl Cre+) to Angiotensin II (AngII: infusion at 1ug/kg/min for 4 weeks) and β-aminopropionitrile (BAPN: administered in drinking water at 0.625mg/ml for 2 weeks) to induce vascular remodeling associated with aortic aneurysm formation. We found that the inner aortic diameter significantly increased (>50%) in Cav1 fl/fl Cre- mice in response to AngII/BAPN. Both outer diameter and vessel wall thickness, while trending towards increased values, were not statistically different in these mice compared to aortas from saline infused mice. These remodeling events were not observed in EC-Cav1 null mice. Immuno-histochemical analysis of vessel cross-sections revealed significant enhancement of macrophage accumulation (F4/80 staining) and expression of MMP2 only within the tunica media of Cav1 fl/fl Cre- aortas exposed to AngII/BAPN. In addition, we found that AngII/BAPN enhanced adhesion molecule expression (ICAM-1/VCAM-1) on the endothelial cell surface of these but not EC-Cav1-/- mice. This observation correlated with activation of the NFkB pathway in cultured rat aortic endothelial cells in response to AngII/BAPN, an event that was abated in cells depleted of Cav1 via pretreatment with a Cav-1 miRNA. These findings indicate that endothelial cell caveolin-1 plays a role in vascular disease through regulation of inflammatory processes that contribute to vascular remodeling.