Acceleration of Diabetic Wound Healing by an Angiopoietin Peptide Mimetic

Angiopathies are one of the leading underlying causes of morbidity in diabetic patients. Poorly managed blood glucose levels contribute to vascular defects that manifest themselves in numerous different clinical conditions, including diabetic retinopathy, nephropathy, peripheral artery disease, and compromised wound healing. The angiopoietin family (Angs 1-4) has been shown to play a critical role in the growth and maintenance of vasculature. Here we evaluate the efficacy of a new Ang-based peptidomimetic compound, Vasculotide, on diabetic-related wound healing. Stimulation of endothelial cells (ECs) with Vasculotide results in activation of the Ang receptor, Tie 2, and its associated signaling pathways. This activation promoted biological responses such as EC survival, migration, and matrix metalloproteinase 2 (MMP2) production. We show that Vasculotide alone and in combination with vascular endothelial growth factor (VEGF) results in the production of well-arborized vessels supported by myogenic cells. Using an excisional skin-wound model produced on the back of diabetic B6.Cg-m(+/+) Lepr(db)/J (db/db) mice, we found that Vasculotide-treated wounds presented with decreased wound closure times (p<0.05) and dramatic increases in granulation tissue (p<0.01). Although the potential of this novel proangiogenic compound in treating microvascular dysfunction is not strictly limited to topical administration, we provide mechanistic evidence as a proof of principle in support of its efficacious use in diabetic wound healing.