Retinoic acid selectively inhibits the vascular permeabilizing effect of VPF/VEGF, an early step in the angiogenic cascade

All-trans-retinoic acid (RA) and other retinoids modulate cell growth and d ifferentiation, generally favoring terminal cell differentiation and inhibi ting carcinogenesis. Retinoids are also reported to inhibit angiogenesis an d endothelial cell migration, actions that are also anti-carcinogenic. vasc ular permeability factor/vascular endothelial growth factor (VPF/VEGF) is a multifunctional cytokine secreted by many tumors. It renders microvessels hyperpermeable to plasma and stimulates endothelial cell migration and divi sion. To investigate further the mechanisms by which RA inhibits angiogenes is, we evaluated the effects of RA on VPF/VEGF-induced angiogenesis and-mic rovascular permeability. RA selectively inhibited the angiogenic response i nduced by VPF/VEGF, but not that induced by fibroblast growth factor-2 (FGF -2), in the CAM assay. RA and two of its isomers also inhibited the vascula r permeabilizing effect of VPF/VEGF but not that induced by histamine. The vascular permeabilization induced by VPF/VEGF and blocked by RA takes place within 1-15 min, too short a time frame for RA to act by modulating transc ription through classic retinoid receptors. RA also inhibited VPF/VEGF-indu ced phosphorylation of PLC-gamma and synthesis of cGMP but actually increas ed VPF/VEGF binding to cultured endothelial cells. Taken together, these fi ndings indicate that RA selectively blocks VPF/VEGF-induced microvascular p ermeability and angiogenesis and also identify VPF/VEGF as a major target o f RA action. The selectivity of RA's action suggests that other, RA-indepen dent pathways must exist for the angiogenesis induced by FGF-2 and the vasc ular permeabilizing effect of histamine. (C) 2000 Academic Press.