Abstract
Background. Although inhibition of angiogenesis represents a beneficial approach for the treatment of various diseases, knowledge about angioinhibitory molecules has been limited. Sphingosine-1-phosphate (S1P) mediates pleiotropic effects in diverse cell types through Edg family receptors. S1P exerts an inhibitory action on cell migration via Edg-5 receptor subtype. We studied whether S1P/Edg-5 system could inhibit angiogenesis. Methods and Results SVEC4-10, a mouse vascular endothelial cell line, possesses the ability to form tube-like structures on the Matrigel. Northern blotting revealed that SVEC4-10 expresses Edg-5 and -3, but not Edg-1. S1P stimulated tube formation and the addition of JTE-013, a specific antagonist against Edg-5, enhanced S1P-induced tube formation. Similarly, JTE-013 potentiated S1P stimulation of cell migration, assessed by a modified Boyden chamber method. In the cells overexpressing Edg-5 (SVEDG5), S1P markedly inhibited epidermal growth factor (EGF)-induced tube formation and migration and the inhibition was reversed by JTE-013. S1P inhibited EGF-induced cellular Rac activation in SVEDG5 cells, and JTE-013 cancelled the S1P inhibition. The Matrigel plug assay in mice revealed that S1P induced angiogenesis in vivo, which was enhanced in the presence of JTE-013. These results suggest that S1P/Edg-5 system plays an inhibitory role in the regulation of angiogenesis, and might be targets of angiostatic and angiogenic therapies. [Jpn J Physiol 55 Suppl:S81 (2005)]
