Retinoids downregulate vascular endothelial growth factor/ vascular permeability factor production by normal human keratinocytes

Normal human keratinocytes (KC) are a prominent source of vascular endothelial growth factor (VEGF)/vascular permeability factor (VPF), both in vivo and in tissue culture. In this report we have investigated the influence of retinoids, which are used to treat several skin diseases, on VEGF/VPF production by KC. All-trans retinoic acid (RA), 13-cis RA, and all-trans retinol reduced VEGF/VPF secretion by KC in primary cultures bya mean ± SD of 58 ± 25%, 46 ± 21%, and 54 ± 20%, respectively, compared with control values. Reductions were observed at concentrations as low as 10^-10 M for alltrans RA, a level that is easily reached in vivo during retinoid treatment. The reduction in VEGF/VPF protein by 10^-6 M all-trans RA was paralleled by a strong down-regulation of VEGF/VPF mRNA levels. In contrast to normal KC, all-trans RA had no effect on the HaCaT keratinocyte cell line, and it stimulated VEGF/VPF release by the epidermoid carcinoma cell line A431 2-fold. Our data demonstrate that retinoids are potent inhibitors of VEGF/VPF production by normal human KC. Down-regulation of VEGF/VPF production in these cells by retinoids may contribute to the therapeutic effects or retinoids in diseases that are accompanied by angioproliferation, such as psoriasis.