(VP121) TREATMENT WITH APELIN AND ANALOGUES IMPROVES WOUND HEALING IN DIABETIC MICE

Background: People with diabetes are uniquely susceptible to diabetic foot ulceration (DFU) and lower extremity amputation (LEA). Indeed, patients with diabetes are more vulnerable to injuries creating hard-to-heal or non-healing wounds and increasing the risk of infection and amputation. Although the complex pathophysiology leading to DFU involves the synergistic effect of multiple mechanical, biological and molecular processes, diabetes impairs the angiogenic process while preventing delivery of oxygen, nutrients and immune proper response to fight the infection. Interestingly, our laboratory has shown that stimulation of the apelinergic system with pyr-apelin-13 (pyr-ape-13) or pyr-ELABELA-32 (pyr-ELA-32) improved blood flow reperfusion in diabetic mice following hind limb ischemia. Our objective is to evaluate the potential therapeutic effect of apelinergic system in a diabetic wound healing model.

METHODS AND RESULTS: Two full-thickness excisional wounds per mice were created on their mid-back, using a 5 mm biopsy punch, in nondiabetic (NDM) and STZ-induced diabetic (DM) mice. Wounds were individually photographed, and laser Doppler perfusion imaging was performed on the day of the surgery and at day 3-7-10 and 14 post-wounding for global wound closure and blood flow perfusion measurements. Daily topical application of pyr-ape-13 and pyr-ELA-32 solution was applied directly on the wounds of DM mice for 14 days. Mice were euthanized at day 14, and wounds were harvested for protein, genes, and histological analysis. Global wound closure was 96% in NDM mice compared to 79% in DM mice. Daily topical application of pyr-ape-13 or pyr-ELA-32 resulted in 92% and 95% of global wound closure in DM mice, respectively. Analysis of histological sections showed several impairments in diabetic wound healing compared to non-diabetic mice such as elevated macrophage infiltration and persistent inflammatory phase as well as decreased blood vessel count. In addition, collagen deposition by fibroblasts and coverage by keratinocytes were delayed in diabetic wounds, suggesting immaturity of the newly formed tissue. Interestingly, pyr-ape-13 or pyr-ELA-32 topical administration in DM mice reduced macrophage infiltration and inflammation, and enhanced blood vessel formation and collagen deposition. In addition, administration of pyr-ape-13 and pyr-ELA-32 in DM mice increased mRNA expression of key growth factors implicated in the angiogenic process (VEGF-A, FGF-2), the extracellular matrix synthesis (TGF-) and epithelialization process (FGF-7, FGF-10).

Conclusion: Treatment with the apelinergic analogs promote several important cellular processes to improve diabetic wound healing.