High Levels of Pigment Epithelium-derived Factor in Diabetes Impair Wound Healing through Suppression of Wnt Signaling.

Diabetic foot ulcer (DFU), caused by impaired wound healing, is a common vascular complication of diabetes. The present study revealed that plasma levels of pigment epithelium-derived factor (PEDF) were elevated in Type 2 diabetic patients with DFU and in db/db mice. To test whether elevated PEDF levels contributes to skin wound healing delay in diabetes, endogenous PEDF was neutralized with an anti-PEDF antibody in db/db mice. Our results showed that neutralization of PEDF accelerated wound healing, increased angiogenesis in the wound skin, and improved functions and numbers of endothelial progenitor cells (EPCs) in the diabetic mice. Further, PEDF deficient mice showed higher baseline blood flow in the skin, higher density of cutaneous micro-vessels, increased skin thickness, improved circulating numbers and functions of EPCs, and accelerated wound healing, compared to the Wt mice. Over-expression of PEDF suppressed the Wnt signaling pathway in the wound skin. Lithium chloride-induced Wnt signaling activation at downstream of the PEDF-interaction site attenuated the inhibitory effect of PEDF on EPCs and rescued the wound healing deficiency in diabetic mice. Taken together, these results suggest that elevated circulating PEDF levels contribute to impaired wound healing on the process of angiogenesis and vasculogenesis through inhibition of Wnt/β-catenin signaling.