Deferoxamine enhances neovascularization and accelerates wound healing in diabetic rats via the accumulation of hypoxia-inducible factor-1α

Aims: Hypoxia-inducible factor (HIF)-1 alpha plays a pivotal role during the process of wound healing. Previous studies reported that deferoxamine (DFO) could increase HIF-1 alpha stability. This study aimed to investigate the effects of DFO on wound healing in diabetic rats and explore the underlying mechanism both in vivo and in vitro. Methods: An excisional diabetic wound model was established and the wound healing among vehicle control, DFO and vascular endothelial growth factor (VEGF) treatment groups was evaluated by macroscopy, histology and Western blot analysis. Human umbilical vein endothelial cells (HUVECs) were treated with DFO or HIF-1 alpha siRNA, and then endothelial tube formation, cell proliferation and migration were examined. Results: DFO-treated wounds exhibited accelerated wound healing with enhanced granulation formation and increased re-epithelialization. Compared to the vehicle or VEGF treatment, DFO significantly increased neovascularization through up-regulation of HIF-1 alpha and target genes including VEGF and stromal cell-derived factor-1 alpha (SDF-1 alpha). DFO failed to stimulate the expression of VEGF and SDF-1 alpha in HUVECs depleted of HIF-1 alpha. In addition, DFO promoted the angiogenic-associated processes of endothelial tube formation, cell proliferation and migration in HIF-1 alpha dependent manner. Conclusions: DFO enhances neovascularization and accelerates diabetic wound healing through the accumulation of HIF-1 alpha and the regulation of endothelial cell function. Crown Copyright (C) 2013 Published by Elsevier Ireland Ltd. All rights reserved.