KERATINOCYTE-DERIVED VASCULAR-PERMEABILITY FACTOR (VASCULAR ENDOTHELIAL GROWTH-FACTOR) IS A POTENT MITOGEN FOR DERMAL MICROVASCULAR ENDOTHELIAL-CELLS

Expression of vascular permeability factor/vascular endothelial growth factor (VPF/VEGF) is markedly increased in the epidermis of lesional psoriatic skin and in healing skin wounds. In this study, we character ized the effects of several cytokines and growth factors on the expres sion and secretion of VPF/VEGF mRNA and protein by cultured human epid ermal keratinocytes, as well as the effect of VPF/VEGF on the growth o f cultured human dermal microvascular endothelial cells. Transforming growth factor-alpha, epidermal growth factor, and phorbol myristate ac etate markedly stimulated VPF/VEGF mRNA expression by cultured keratin ocytes; as in psoriatic skin, the three most common VPF/VEGF isoforms (encoding proteins of 121, 165, and 189 amino acids) were upregulated to an equal extent. Transforming growth factor (TGF)-alpha, epidermal growth factor, and phorbol myristate acetate also enhanced the secreti on of VPF/VEGF by keratinocytes; in contrast, a number of other cytoki nes including interleukin (IL)-1, IL-6, IL-8, tumor necrosis factor-al pha, interferon-gamma, and transforming growth factor-beta did not ind uce VPF/VEGF secretion. The VPF/VEGF secreted by keratinocytes was bio logically active in that, like recombinant human VPF/VEGF, it potently stimulated dermal endothelial cell proliferation. Scatchard analysis revealed two high-affinity VPF/VEGF binding sites on dermal endothelia l cells with dissociation constants of 51 pM and 2.9 pM. These results suggest that the avascular epidermis has the capacity to regulate der mal angiogenesis and microvascular permeability by a paracrine mechani sm involving the secretion of VPF/VEGF. Similar mechanisms may be anti cipated in a variety of inflammatory and neoplastic skin diseases char acterized by microvascular hyperpermeability, edema, and angiogenesis.