Figure 2: Negative impact of high glucose levels and failure of the insulin system on vascular cells. Endothelial cells are a sensitive target for high glucose concentration and especially for the insulin receptor downstream signaling attenuation. Similarly, pericytes, which are key cells for the angiogenic process to succeed, are targeted by these factors. The endothelial cells metabolic response to the above proximal triggers engenders the accumulation of superoxide and hydroxyl reactive groups. These prooxidative elements disrupt the physiological pathways for NO metabolism, accumulating toxic nitrosylation end-products. In this context, AGEs are precipitately formed and accumulated within the vascular wall. Different pathways converge to induce TNF-α overproduction. The proximal triggers and all these factors also contribute to disrupt e-NOS activity having as net result a deficit in endothelial NO, the inability for vasodilation, and the suppression of endothelial cells proliferative reserves. This circle is further amplified due to the concomitant reduction in the pool of critical angiogenic factors involved in the regulation of vascular regeneration. Eventually endothelial cells and pericytes may onset a pro-apoptogenic program, which will hinder granulation tissue perfusion and wound healing.