Abstract 15395: Caveolin-1 is a Primary Determinant of Endothelial Stiffening Associated With Dyslipidemia, Disturbed Flow and Ageing

Abstract

Objective: Endothelial stiffness is emerging as a major determinant in endothelial function. Here, we analyzed the role of caveolin-1 (Cav-1) in determining the stiffness of endothelial cells exposed to oxidized low density lipoprotein (oxLDL) under static and hemodynamic conditions in vitro and of aortic endothelium in vivo in mouse models of dyslipidemia and ageing. Approach and Results: Elastic moduli of cultured endothelial cells and of endothelial monolayer of freshly isolated mouse aortas were measured using atomic force microscopy. We found that a loss of Cav-1 abrogates the uptake of oxLDL (n=5-8) and oxLDL-induced endothelial stiffening (n=4-5) but has no effect on endothelial stiffness in the absence of oxLDL (n=4). A loss of Cav-1 also abrogated endothelial stiffening induced by disturbed flow, which in turn is oxLDL dependent (n=6). Mechanistically, Cav-1 is required for the expression of CD36 (cluster of differentiation 36) scavenger receptor (n=4) but not for endothelial stiffening induced by a direct application of 7ketocholesterol (n=8). Genetic deletion of Cav-1 also led to profound changes in endothelial stiffness in vivo : it abrogated endothelial stiffening observed in the disturbed flow region of the aortic arch (n=5-6), abrogated endothelial stiffening induced by feeding the mice high fat diet (4-6 weeks, n=5) and significantly blunted endothelial stiffening that develops with advanced age (n=5-6). This effect was independent of stiffening of the sub-endothelium layer (n=5-8). Conclusions: Taken together, this study demonstrates that Cav-1 plays a critical role in endothelial stiffening induced by oxLDL in vitro and by dyslipidemia, disturbed flow and ageing in vivo . Mechanistically, Cav-1 regulates endothelial stiffening via CD36-mediated uptake of oxLDL, whereas exposure to 7ketocholesterol circumvents this step.