Suppression of Receptor for Advanced Glycation End Products Improves Angiogenic Responses to Ischemia in Diabetic Mouse Hindlimb Ischemia Model

Background. The role of the receptor for advanced glycation end products (RAGE) for the impaired angiogenic response in diabetic patients is not well known. We investigated the impact of RAGE suppression by soluble RAGE (sRAGE) on the angiogenic response in a diabetic hindlimb ischemia mouse model. Materials and Methods. Hindlimb ischemia model was prepared by ligation of femoral artery in diabetic and nondiabetic mice. Ischemia-induced angiogenic response was evaluated by laser-Doppler perfusion imaging, muscle capillary density, and protein expression of vascular endothelial growth factor (VEGF) and high-mobility group box (HMGB)-1. Results. Diabetic mice showed attenuated recovery of ischemic limb perfusion on laser-Doppler perfusion imaging compared with nondiabetic mice. The treatment with sRAGE significantly improved blood flow in the ischemic limbs of diabetic mice. The expression levels of VEGF and HMGB-1 in the limb muscle tissues of diabetic mice were lower than in those of nondiabetic mice. The treatment with sRAGE significantly increased the VEGF and HMGB-1 protein expression in the ischemic limb muscle tissues in the diabetic mice. Conclusion. The suppression of RAGE by sRAGE administration improved angiogenic response to ischemia in diabetic mice and was associated with increased HMGB-1 and VEGF levels in muscle tissues.