EDN1 and endothelial dysfunction: Importantly, endothelial dysfunction (and its underlying mechanisms) appears to be a dynamic process during disease progression, as evidenced by two studies employing the same model of DM and hypercholesterolemia, demonstrating a shift from early (2.5 months) loss of NO-mediated vasodilation [72] to a late (15 months) normalization of NO signalling but increased vasoconstriction to endothelin-1 [64].