Negative regulation of endothelial morphogenesis and angiogenesis by S1P2 receptor

We speculated that the sphingosine-1-phosphate (S1P) receptor S1P2, which uniquely inhibits cell migration, might mediate inhibitory effects on endothelial cell migration and angiogenesis, different from S1P1 and S1P3. Mouse vascular endothelial cells, which endogenously express S1P2 and S1P3, but not S1P1, responded to S1P and epidermal growth factor (EGF) with stimulation of Rac, migration, and the formation of tube-like structures on the Matrigel. The S1P3-antagonist VPC-23019 abolished S1P-induced, Gi-dependent Rac stimulation, cell migration, and tube formation, whereas the S1P2-antagonist JTE-013 enhanced these S1P-induced responses, suggesting that S1P2 exerts inhibitory effects on endothelial Rac, migration, and angiogenesis. S1P2 overexpression markedly augmented S1P-induced, Gi-independent inhibition of EGF-induced migration and tube formation. Finally, the blockade of S1P2 by JTE-013 potentiated S1P-induced stimulation of angiogenesis in vivo in the Matrigel implant assay. These observations indicate that in contrast to S1P1 and S1P3, S1P2 negatively regulates endothelial morphogenesis and angiogenesis most likely through down-regulating Rac.