A two-hit model of vascular perturbation. Stage 1 shows the interaction between AGEs, modified biochemical species and their receptors (RAGEs), transmembrane protein receptors of the Ig family present at low levels on a range of cells including ECs in addition to macrophages (Mfs), smooth muscle cells, and neurons. AGEs may perturb the normal physiologic function of the modified species and thus alter the EC's normal vascular functions. Stage 2 details subsequent perturbations resulting from the superimposed stimuli of accumulated lipoprotiens as seen in atherosclerotic lesions, foreign materials that may be seen in wound repair, and bacterial infection that may be seen in periodontal disease.