D. Altavilla et al., Inhibition of lipid peroxidation restores impaired vascular endothelial growth factor expression and stimulates wound healing and angiogenesis in thegenetically diabetic mouse, DIABETES, 50(3), 2001, pp. 667-674
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 defici
t by using an incisional skin-wound model produced on the back of female di
abetic C57BL/KsJ db+/ db+ mice and their normal (dB+/+m) littermates. Anima
ls were then randomized to the following treatment: raxofelast (15 mg . kg(
-1) . day(-1) i.p.), an inhibitor of lipid peroxidation, or its vehicle (DM
SO/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 s
tudied the time course of VEGF mRNA expression throughout the skin-repair p
rocess (3, 6, and 12 days after skin injury), by means of reverse transcrip
tase-polymerase chain reaction, as well as the mature protein in the wounds
. Diabetic mice showed impaired wound healing with delayed angiogenesis, lo
w breaking strength, and increased wound CD content when compared with thei
r normal littermates. In healthy control mice, a strong induction of VEGF m
RNA was found between day 3 and day 6 after injury, while no significant VE
GF mRNA expression was observed at day 12 after injury. In contrast, VEGF m
RNA 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 co
ntent of the angiogenic factor was markedly changed in diabetic mice. Admin
istration of raxofelast did not modify the process of wound repair in norma
l mice, but significantly improved the impaired wound healing in diabetic m
ice through the stimulation of angiogenesis, re-epithelization, and synthes
is and maturation of extracellular matrix. Moreover, raxofelast treatment s
ignificantly reduced wound CD levels and increased the breaking strength of
the wound. Lastly, the inhibition of lipid peroxidation restored the defec
t in VEGF expression during the process of skin repair in diabetic mice and
normalized the VEGF wound content. The current study provides evidence tha
t lipid peroxidation inhibition restores wound healing to nearly normal lev
els in experimental diabetes-impaired wounds and normalizes the defect in V
EGF regulation associated with diabetes-induced skin-repair disorders.