REGULATION OF VASCULAR ENDOTHELIAL GROWTH-FACTOR EXPRESSION IN CULTURED KERATINOCYTES - IMPLICATIONS FOR NORMAL AND IMPAIRED WOUND-HEALING

Recent in situ hybridization studies had demonstrated a strong increas e in vascular endothelial growth factor (VEGF) mRNA expression in the hyperproliferative epithelium during wound healing. To determine poten tial mediators of VEGF induction during this process, we analyzed the regulation of VEGF expression in cultured human keratinocytes, We foun d a large induction of VEGF expression upon treatment of quiescent cel ls with serum, epidermal growth factor, transforming growth factor-bet a 1, keratinocyte growth factor, or the proinflammatory cytokine tumor necrosis factor alpha, respectively, Since all these factors are pres ent at the wound site during the early phase of wound healing, they mi ght also be responsible for VEGF induction after cutaneous injury. To determine the importance of increased VEGF production for wound repair , we compared the time course of VEGF mRNA expression during wound hea ling of healthy control mice with the kinetics of VEGF expression duri ng skin repair of genetically diabetic db/db mice which are characteri zed by impaired wound healing, In normal mice we found elevated VEGF m RNA levels during the period when granulation tissue formation occurs. In contrast, VEGF mRNA levels even declined during this period in db/ db mice, suggesting that a defect in VEGF regulation might be associat ed with wound healing disorders.