The apelinergic system accelerates wound healing in both type 1 and 2 diabetic mice

Chronic wounds are a serious complication of diabetes. Multiple components in the healing process are impaired by diabetes, creating hard-to-heal or non-healing wounds, and increasing the risk of infection, enlargement, and amputation. Altered angiogenesis is a major contributor to the delayed healing process in diabetic wounds. The apelinergic system (APJ/Apelin/ELABELA) is an activator of the angiogenic response in endothelial cells, and apelin treatment has been shown to improve vascular density in animal models of ischemia. This study explored the impact of Pyr-ape-13 and Pyr-ELA-32 on wound healing processes in type 1 and type 2 diabetic mice and on fibroblast function. Two full-thickness excisional wounds were created on the mid-back of type 1 and type 2 diabetic mice who received daily topical application of Pyr-ape-13 or Pyr-ELA-32 for 14 days. The global wound closure and healing process were evaluated. Cultured fibroblasts were exposed to normal or high glucose levels and hypoxia. Cell migration and proliferation assays were performed following either Pyr-ape-13 or Pyr-ELA-32 stimulation. Fourteen days post-injury, global wound closure was improved in both diabetic mouse models receiving Pyr-ape-13 or Pyr-ELA-32 compared to untreated diabetic mice. Wound treatment with Pyr-ape-13 and Pyr-ELA-32 improved re-epithelialization and angiogenesis, reduced inflammation, and promoted collagen synthesis in diabetic scar tissue. In cultured mouse and human fibroblasts, Pyr-ape-13 and Pyr-ELA-32 stimulation induced cell migration, proliferation and Akt/ERK signaling pathways under normal and high glucose concentrations and hypoxia exposure. In conclusion, our results demonstrated the therapeutic potential of the endogenous ligands of APJ, apelin, and ELABELA, for the treatment of diabetic wounds.