Schematic depiction of a two-hit model of vascular perturbation mediated by RAGE and its ligands. We hypothesize that the diabetic vessel wall displays increased expression of RAGE ligands and the receptor itself (first hit). In the presence of additional perturbation (second hit), such as ischemic stress, immune/inflammatory stimuli, physical stress, or modified lipoproteins, there is an exaggerated cellular response promoting formation of vascular lesions (rather than restitution of vascular homeostasis).