Retinoids induce fibroblast growth factor-2 production in endothelial cells via retinoic acid receptor alpha activation and stimulate angiogenesis invitro and in vivo

The effect of retinoic acid (RA) on endothelial cells is still controversia l and was examined in the present study. In bovine aortic endothelial cells (BAECs), all-trans RA (ATRA) and 9-cis RA (9CRA), but not 13-cis RA (13CRA ), induced fibroblast growth factor-2 (FGF-2) production and exhibited a bi phasic dose-dependent effect to enhance BAEC proliferation and differentiat ion into tubular structures on reconstituted basement membrane proteins (Ma trigel); both processes were inhibited by FGF-2-neutralizing antibody. The pan RA receptor (RAR)-selective ligand (E)-4-[2-(5,5,8,8,-tetramethyl-5,6,7 ,8-tetrahydro-2-naphtalenyl)-1-propenyl] benzoic acid and the RAR alpha -se lective ligand 4-[1-(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydro-2-naphtyl)-et henyl] benzoic acid stimulated the production of FGF-2, whereas the additio n of the RAR alpha -antagonist RO 41-5253 inhibited this effect. In BAECs, the forced expression of RAR alpha, but not RAR beta or RAR gamma, enhanced FGF-2 production, whereas the RAR alpha -dominant negative, Delta 403, blo cked this effect. Furthermore, RAR alpha overexpression directly stimulated BAEC differentiation on Matrigel and potentiated the effects of ATRA in th is assay. Finally, ATRA-treated BAECs coinjected with Matrigel subcutaneous ly in mice induced neovascularization within the Matrigel plug, and ATRA al so enhanced angiogenesis in the chicken chorioallantoic membrane assay. In conclusion, RA can stimulate endothelial cell proliferation and differentia tion in vitro via enhanced RAR alpha -dependent FGF-2 production, and it ca n also induce angiogenesis in vivo.