119 Differential Regulation of Angiogenic Genes in Normal and Diabetic Wound Healing

Abstract

Wound healing is a complicated biological process that involves interactions of multiple cell types, various growth factors, their mediators and the extracellular matrix proteins. In this study, we have studied the differential regulation of angiogenic genes during wound healing in transgenic diabetic mice and non-diabetic mice. One 8 mm full thickness cutaneous wound under aseptic conditions was created on either side of the midline. Wound tissues were studied at 4, 7, and 11 days postwounding and healing was assessed by histology. The pathway specific gene expression profile of wound tissue in transgenic diabetic mice was compared with the normal mice. Profiling of these genes showed differential regulation of many angiogenic promoters, inhibitors, growth factors and cytokines. Furthermore, in our study hypoxia inducible factor (HIF-1a), osteopontin (OPN) and osteonectin are induced early at day 4, in both the diabetic and nondiabetic wound. The expression was downregulated by 11-day postwounding in the nondiabetic wound, whereas diabetic wounds showed constitutively high expression of these genes. The expression patterns of these genes were concomitant with the extent of healing as assessed by histology at different time point postwounding. These results suggest wound healing is a complex process that involves cascade of interaction of various factors. Although a single gene may not be solely responsible for any impairment in healing; however, an in-depth study of these genes and precise balance between the inducers and inhibitors of angiogenesis may provide an answer to the delayed healing in diabetic conditions. (This work was supported by a grant (5 R21 AT000517-02) from the NCCAM, National Institute of Health, Bethesda, MD.)