High Glucose Inhibits the AMPK-AKT2-ATF-2-MMP2 Pathway and Endothelial Cell Migration

There are numerous deleterious effects of repeated bouts of acute high glucose (HG) or chronic HG. At the molecular level, HG causes oxidative stress, increases advanced glycation end products which activate their cognate receptors (AGE/RAGE), and activate pro-inflammatory pathways. At the physiological level, tooth decay (lactic acid demineralization of enamel), gum disease, obesity (pro-inflammatory cytokines, adipokines), erectile dysfunction, vaginal infections result from HG. Important to this project, HG damages blood vessels leading to the cardiovascular complications in diabetes. HG accelerates macrovascular disease increase risk of strokes, myocardial infarction and renal failure. Further, HG promotes an increased susceptibility to dermal breakdown, forming a portal of entry for microbial infections. This is accompanied by inadequate wound healing of decubitus ulcers, trauma/accident-induced injury or cutaneous infections.An integral component of wound healing is the process of neovascularization or reperfusion of the injured or ischemic area to supply necessary nutrients and for removal of necrotic or damaged cells and debris. A primary component of neovascularization is endothelial cell (EC) migration to sites of injury. It is well established that HG conditions result in disturbed endothelial migration and wound healing. My specific aim is to delineate the molecular mechanisms of the HG impaired EC migration. The working hypothesis of this project it that high glucose inhibits the pro-angiogenic AMP-activated kinase, thereby inhibiting matrix metaloproteinase-2 collagen cleavage and matrix degradation, which under physiological glucose levels, facilitates wound healing through neovascularization. This pathway is mediated by the phosphorylation and activation of AKT2 (protein kinase B-â), which subsequently increases activating transcription factor 2 (ATF-2) binding to the MMP-2 promoter to increases its expression and activity