LDL receptors, caveolae and cholesterol in endothelial dysfunction: oxLDLs accomplices or victims?

Oxidized LDLs (oxLDLs) and oxysterols play a key role in endothelial dysfunction andthe development of atherosclerosis. The loss of vascular endothelium functionnegatively impacts vasomotion, cell growth, adhesiveness and barrier functions.While for some of these disturbances, a reasonable explanation can be provided froma mechanistic standpoint, for many others, the molecular mediators that are involvedare unknown. Caveolae, specific plasma membrane domains, have recently emergedas targets and mediators of oxLDL-induced endothelial dysfunction. Caveolae andtheir associated protein caveolin-1 (Cav-1) are involved in oxLDLs/LDLs transcytosis,mainly through the scavenger receptor class B type 1 (SR-B1 or SCARB1). In contrast,oxLDLs endocytosis is mediated by the lectin-like oxidized LDL receptor 1 (LOX-1),whose activity depends on an intact caveolae system. In addition, LOX-1 regulatesthe expression of Cav-1 and vice versa. On the other hand, oxLDLs may affectcholesterol plasma membrane content/distribution thus influencing caveolaearchitecture, Cav-1 localization and the associated signalling. Overall, the evidenceindicate that caveolae have both active and passive roles in oxLDL-inducedendothelial cell dysfunction. First, as mediators of lipid uptake and transfer in thesubendothelial space and, later, as targets of changes in composition/dynamics ofplasma membrane lipids resulting from increased levels of circulating oxLDLs. Gaininga better understanding of how oxLDLs interact with endothelial cells and modulatecaveolae-mediated signalling pathways, leading to endothelial dysfunction, iscrucial to find new targets for intervention to tackle atherosclerosis and the relatedclinical entities.