Caveolin-1 is a primary determinant of endothelial stiffening associated with dyslipidemia, disturbed flow, and ageing

Abstract

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 (EC) 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. Elastic moduli of cultured ECs and of the endothelial monolayer of freshly isolated mouse aortas were measured using atomic force microscopy (AFM). We found that a loss of Cav-1 abrogates the uptake of oxLDL and oxLDL-induced endothelial stiffening, as well as endothelial stiffening induced by disturbed flow (DF), which was also oxLDL dependent. Mechanistically, Cav-1 is required for the expression of CD36 (cluster of differentiation 36) scavenger receptor. Genetic deletion of Cav-1 abrogated endothelial stiffening observed in the DF region of the aortic arch, and induced by a high fat diet (4–6 weeks) and significantly blunted endothelial stiffening that develops with advanced age. This effect was independent of stiffening of the sub-endothelium layer. Additionally, Cav-1 expression significantly increased with age. No differences in elastic modulus were observed between the sexes in advanced aged wild type and Cav-1 knockout mice. 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.