025Modulation of Wound Repair in the Obese Diabetic Mouse: a Role for VEGF Gene Transfer

Identifying molecular loci of impaired cutaneous healing in diabetes with an eye towards developing targeted therapy to ameliorate dysrepair continues to evolve as a promising area of study. By using an excisional wound model produced on the dorsum of female diabetic C57BL/KsJ db  + / db + mice as well as their normal (WT) & heterozygous (HZ) littermates, we studied the effects of peri‐wound intradermal injection of adeno‐associated viral vector (AAV) expressing the 165‐amino acid isoform of human vascular endothelial growth factor (VEGF) on the following: kinetics of re‐epithelialization, neoangiogenesis and granulation tissue formation, matrix remodelling, collagen deposition, and maturation. One sq. in. full thickness excisional wound was created in the mid‐upper back, rendering half of the wound as either right or left paravertebral. Animals were randomized to receive 1 of 3 treatments via intradermal injection: 1)VEGF (AAV) vector; 2)Adnull vector; 3)PBS. Postoperatively, wounds were examined & photographed on Days 3, 7, 10, 14, 21 & 28. Also, tissue was harvested for histology & immunohistochemistry (PECAM), and snap frozen for protein & RNA analysis. A scoring system was used to grade re‐epithelialization, granulation tissue thickness, matrix density, inflammation, vascular density, epithelial maturity. AAV‐VEGF exerted minimal effect on repair in WT and HZ mice. However, pronounced neovascularization, thickened granulation tissue & increased matrix deposition was noted after VEGF treatment in the db/db mice compared to those that received PBS or adnull vector at all timepoints. While the induction of angiogenesis in VEGF treated db/db mice lagged behind the unimpaired mice by 5–7 days, a global improvement in wound healng was observed.
R Crystal, Dir Inst Genetic Medicine, Weill Med College‐Cornell Univ