Background Severe hindlimb ischemia is a chronic disease with poor prognosis that can lead to amputation or even death. This study aimed to assess the therapeutic effect of liraglutide on hind‐limb ischemia in type 2 diabetic mice and to elucidate the underlying mechanism. Methods and Results Blood flow reperfusion and capillary densities after treatment with liraglutide or vehicle were evaluated in a mouse model of lower‐limb ischemia in a normal background or a background of streptozotocin‐induced diabetes. The proliferation, migration, and tube formation of human umbilical vein endothelial cells were analyzed in vitro upon treatment with liraglutide under normal‐glucose and high‐glucose conditions. Levels of phospho‐Akt, phospho‐endothelial nitric oxide synthase, and phospho‐extracellular signal‐related kinases 1 and 2 under different conditions in human umbilical vein endothelial cells and in ischemic muscle were determined by western blotting. Liraglutide significantly improved perfusion recovery and capillary density in both nondiabetic and diabetic mice. Liraglutide also promoted, in a concentration‐dependent manner, the proliferation, migration, and tube formation of normal glucose– and high glucose–treated human umbilical vein endothelial cells, as well as the phosphorylation of Akt, endothelial nitric oxide synthase, and extracellular signal‐related kinases 1 and 2 both in vitro and in vivo. The liraglutide antagonist exendin (9–39) reversed the promoting effects of liraglutide on human umbilical vein endothelial cell functions. Furthermore, exendin (9–39), LY294002, and PD98059 blocked the liraglutide‐induced activation of Akt/endothelial nitric oxide synthase and extracellular signal‐related kinases 1 and 2 signaling pathways. Conclusions These studies identified a novel role of liraglutide in modulating ischemia‐induced angiogenesis, possibly through effects on endothelial cell function and activation of Akt/endothelial nitric oxide synthase and extracellular signal‐related kinases 1 and 2 signaling, and suggested the glucagon‐like peptide‐1 receptor may be an important therapeutic target in diabetic hind‐limb ischemia.

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