The PI3K/A-t pathway mediated by insulin for vasodilation is inhibited, leading to decreased endothelial nitric oxide synthase (eNOS) activity and reduced NO production, whereas the MAPK pathway is overly activated, resulting in increased endothelin-1 (ET-1), causing sustained vasoconstriction and endothelial dysfunction [47]. Here, NOS3 is linked to endothelial dysfunction.