Using HFD ad libitum-fed KSR2−/− mice, HFD pair-fed Apoe−/−KSR2−/− mice and AAV9-KSR2 endothelium-specific overexpression models, we demonstrated that endothelial KSR2 regulates atherosclerosis progression independently of systemic lipid and glucose alterations. This evidence concerns the gene KSR2 and atherosclerosis.