Impaired wound healing is a well-documented phenomenon in experimental and clinical diabetes. Experimental evidence suggests that a defect in
vascular endothelial growth factor (
VEGF) regulation might be associated with wound-healing disorders. We studied the involvement of lipid peroxidation in the pathogenesis of altered
VEGF expression in diabetes-related healing deficit by using an incisional skin-
wound model produced on the back of female diabetic C57BL/KsJ db+/ db+ mice and their normal (db+/+m) littermates. Animals were then randomized to the following treatment:
raxofelast (15 mg.kg(-1).day(-1) i.p.), an inhibitor of lipid peroxidation, or its vehicle (
DMSO/NaCl 0.9%, 1:1 vol: vol). The animals were killed on different days (3, 6, and 12 days after skin injury), and the wounded skin tissues were used for histological evaluation, for analysis of conjugated dienes (CDs), as an index of lipid peroxidation and
wound breaking strength. Furthermore, we studied the time course of
VEGF mRNA expression throughout the skin-repair process (3, 6, and 12 days after skin injury), by means of
reverse transcriptase-polymerase chain reaction, as well as the mature
protein in the
wounds. Diabetic mice showed impaired wound healing with delayed angiogenesis, low breaking strength, and increased
wound CD content when compared with their normal littermates. In healthy control mice, a strong induction of
VEGF mRNA was found between day 3 and day 6 after injury, while no significant
VEGF mRNA expression was observed at day 12 after injury. In contrast,
VEGF mRNA levels, after an initial increase (day 3), were significantly lower in diabetic mice than in normal littermates, and light induction of
VEGF mRNA expression was also present at day 12 after injury. Similarly, the
wound content of the
angiogenic factor was markedly changed in diabetic mice. Administration of
raxofelast did not modify the process of
wound repair in normal mice, but significantly improved the impaired wound healing in diabetic mice through the stimulation of angiogenesis, re-epithelization, and synthesis and maturation of extracellular matrix. Moreover,
raxofelast treatment significantly reduced
wound CD levels and increased the breaking strength of the
wound. Lastly, the inhibition of lipid peroxidation restored the defect in
VEGF expression during the process of skin repair in diabetic mice and normalized the
VEGF wound content. The current study provides evidence that lipid peroxidation inhibition restores wound healing to nearly normal levels in experimental diabetes-impaired
wounds and normalizes the defect in
VEGF regulation associated with diabetes-induced skin-repair disorders.