Local Injection of Deferoxamine Improves Neovascularization in Ischemic Diabetic Random Flap by Increasing HIF-1α and VEGF Expression

Abstract

BackgroundAlthough the systemic administration of deferoxamine (DFO) is protective in experimental models of normal ischemic flap and diabetic wound, its effect on diabetic flap ischemia using a local injection remains unknown.ObjectiveTo explore the feasibility of local injection of DFO to improve the survival of ischemic random skin flaps in streptozotocin (STZ)-induced diabetic mice.MethodsIschemic random skin flaps were made in 125 mice. Animals were divided into the DFO-treated (n = 20), PBS-treated (n = 16) and untreated (n = 16) groups. Surviving area, vessel density, and expression of vascular endothelial growth factor (VEGF) and hypoxia-inducible factor-1α (HIF-1α) were evaluated on the seventh day after local injection.ResultsThe viability of DFO-treated flap was significantly enhanced, with increased regional blood perfusion and capillary density compared with those in the two control groups. Fluorescence-activated cell sorting (FACS) analysis demonstrated a marked increase in systemic Flk-1+/CD11b− endothelial progenitor cells (EPCs) in DFO-treated mice. Furthermore, the expression of VEGF and HIF-1α was increased not only in diabetic flap tissue, but also in dermal fibroblasts cultured under hyperglycemic and hypoxic conditions.ConclusionsLocal injection of DFO could exert preventive effects against skin flap necrosis in STZ-induced diabetic mice by elevating the expression of HIF-1α and VEGF, increased EPC mobilization, which all contributed to promote ischemic diabetic flap survival.

VEGF released by deferoxamine preconditioned mesenchymal stem cells seeded on collagen-GAG substrates enhances neovascularization

“…Wang et al . showed that local injections of DFO enhanced healing in diabetic skin flaps in mice, similar to non-diabetic animals, through an increased production of HIF-1α and VEGF20. Hou et al .…”

Deferoxamine: potential novel topical therapeutic for chronic wounds

“…DFO prevented the methylglyoxal modification of p300, which has been shown to impact negatively on the heterodimerization of the two HIF‐1 subunits . Additionally, local injection of DFO into ischaemic flaps of diabetic mice resulted in wound healing enhancement and prevention of flap necrosis by increasing HIF‐1α and VEGF expression, endothelial cell recruitment and neovascularization …”

Topical application of nitrosonifedipine, a novel radical scavenger, ameliorates ischemic skin flap necrosis in a mouse model

“…16 Briefly, 500 ml of nifedipine solution (10 mmol/L) in methanol was placed in a glass beaker and then exposed to a halogen light (500W, Kodak Ektagraphic III Projector, Kodak, Rochester, NY) with constant stirring. The eluent corresponding to newly observed peaks was collected and evaporated for determination of its structure by 1 H-NMR, 13 C-NMR, IR, and ESI-MS. After 18 hours of irradiation under our experimental conditions, nifedipine had been completely converted to NO-NIF with a purity of more than 99%.…”

“…Actually, use of superoxide dismutase (SOD), an endogenous scavenger of the superoxide radical, increased flap survival . Other antioxidative drugs have also successfully been applied to protect against flap necrosis in animal models …”

“…1,2 Other antioxidative drugs have also successfully been applied to protect against flap necrosis in animal models. [10][11][12][13][14][15] Nitrosonifedipine [2,6-dimethyl-4-(2-nitrosophenyl)23,5pyridinedicarboxylic acid dimethyl ester] (NO-NIF) is a nitroso analog of nifedipine which is an L-type Ca2 1 -channel blocker. NO-NIF is highly reactive to lipid-derived radicals in vitro, and participates in ROS radical scavenging activity at the cell membrane.…”