HYPOXIA REGULATES THE EXPRESSION OF VASCULAR-PERMEABILITY FACTOR VASCULAR ENDOTHELIAL GROWTH-FACTOR (VPF VEGF) AND ITS RECEPTORS IN HUMAN SKIN/

Tissue hypoxia is a characteristic feature of malignant tumors and hea ling wounds, conditions that are associated with angiogenesis and with increased expression of vascular permeability factor (VPF; also calle d vascular endothelial growth factor, VEGF), a selective endothelial c ell mitogen inducing microvascular hyperpermeability in vivo. We inves tigated the regulation of VPF/VEGF and its receptors by tissue hypoxia in normal human skin explants and in cultured skin cells ill vitro, V PF/VEGF mRNA expression was dramatically upregulated in epidermal kera tinocytes, dermal fibroblasts, and dermal microvessels after 24 h of s kin organ culture, Hypoxia also enhanced the expression of VPF/VEGF in cultured epidermal keratinocytes and dermal microvascular endothelial cells (predominantly VPF/VEGF(121) and VPF/VEGF(165)) and in dermal f ibroblasts (additional upregulation of VPF/VEGF(189)). The expression of the VPF/VEGF receptor Flt-1 was selectively induced on dermal micro vessels in skin explant cultures and in dermal endothelial cell monola yer cultures under hypoxic conditions. In contrast, the KDR receptor w as downregulated by hypoxia, These results suggest that hypoxia likely regulates cutaneous angiogenesis and microvascular permeability by tw o distinct mechanisms: (i) Induction of VPF/VEGF in epithelial and mes enchymal cells, including endothelial cells. (ii) Differential modulat ion of VPF/VEGF receptor expression by microvascular endothelial cells . These mechanisms may be of importance in the pathogenesis of healing wounds and some malignant tumors that are commonly characterized by h ypoxia and overexpression of VPF/VEGF.