The apelinergic system accelerates skin repair of full-thickness excisional wounds in a diabetic murine model

Abstract Introduction: 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, increasing the risk of infection, enlargement and amputation. Altered angiogenesis is a major contributor of delayed healing process in diabetic wounds. The apenilergic 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-apelin-13 and Pyr-ELABELA-32 on wound healing processes in diabetic mice and on fibroblast function. Methods: Two full-thickness excisional wounds were created on the mid-back of nondiabetic and diabetic mice. Diabetic mice received topical application of Pyr-apelin-13 or Pyr-ELABELA-32 daily for 14 days, and wounds were individually photographed to measure global wound closure and healing process. In vitro, fibroblasts were exposed to normal (NG) or high glucose (HG) levels and hypoxia. Cell migration and proliferation assays were performed following either Pyr-apelin-13 or Pyr-ELABELA-32 stimulation. Results: Fourteen days post-injury, global wound closure was improved in diabetic mice receiving Pyr-apelin-13 or Pyr-ELABELA-32 compared to untreated diabetic mice. Wound treatment with Pyr-apelin-13 and Pyr-ELABELA-32 improved re-epithelialization and angiogenesis, reduced inflammation and promoted collagen synthesis in diabetic scar tissue. In cultured fibroblasts, Pyr-apelin-13 and Pyr-ELABELA-32 stimulation induced cell migration and proliferation through Akt and ERK signaling pathways under both NG or HG concentrations and hypoxia exposure. Conclusion: Our results demonstrated the therapeutic potential of the endogenous ligands of APJ, apelin and ELABELA, for the treatment of diabetic wounds.