UV radiation and prostaglandin E2 up-regulate vascular endothelial growth factor (VEGF) in cultured human fibroblasts

Objective and Design: Exposure to UV radiation is responsible for skin eryt hema and inflammation. PGE2 is an important inflammatory mediator involved in this process and vascular endothelial growth factor (VEGF) is a potent v ascular permeability factor mainly produced by epidermal keratinocytes. Thi s study was aimed at determining whether UVB/A I radiation and prostaglandi n E2 (PGE2) could modulate the production of VEGF by cultured dermal human fibroblasts (HF) in comparison to keratinocytes (HK). Materials and Methods: The skin cells derived from foreskin, were cultured in defined medium before treatment by either UVB/A I radiation, or stimulat ion by addition of PGE2 (10(-8) to 10(-5) M). The expression of VEGF in cul tured fibroblasts and keratinocytes was evaluated at the mRNA (RT-PCR) and protein levels (ELISA). Results: The basal level of VEGF was lower in HF than in HK. Both UVB and U VA1 radiation strongly up-regulated VEGF mRNA and protein in HF whereas UVB but not UVA I radiation induced a VEGF increase in HK only at the protein level. UVA1, when associated with UVB radiation, showed an additive effect on VEGF secretion in HF but not in HK. PGE2 increased in a dose-dependent m anner the expression of VEGF in HF but not in HK. Indomethacin as well as t he antioxidant a-tocopherol did not reduce UV-induced enhanced secretion of VEGF by both fibroblasts and keratinocytes whereas pyrolidine dithiocarbam ate exerted an inhibition of this overexpression. Conclusions: These results indicate different signaling pathways in the PGE 2 and UV-induced regulation of VEGF in dermal fibroblasts and epidermal ker atinocytes. They also suggest a role for VEGF from both fibroblasts and ker atinocytes in the UV-induced erythema, independent of PGE2. A dermal overex pression of VEGF by fibroblasts from UV-irradiated skin may contribute to d ilated microvasculature. a feature of skin photoaging and more generally, t o a more permissive stroma to tumor formation than unexposed skin.