Diabetic and hypercholesterolaemic Ins2+/Akita: ApoE−/− mice develop aortic stiffening, associated with up‐regulation of hypertonicity‐responsive gene such as AQ1 and NFAT5, along with genes implicated in early inflammation and atherosclerosis, such as VCAM‐1; cytoskeletal remodelling, such as F‐actin and ASMA; endothelial dysfunction, such as iNOS and eNOS; and ROS generation such as NADPH oxidase. Here, ACTA1 is linked to endothelial dysfunction.