The Sphingosine-1-phosphate Receptors S1P1, S1P2, and S1P3 Function Coordinately during Embryonic Angiogenesis*

Sphingosine-1-phosphate (S1P) elicits diverse cellular responses through a family of G-protein-coupled receptors. We have shown previously that genetic disruption of the S1P1 receptor, the most widely expressed of the family, results in embryonic lethality because of its key role within endothelial cells in regulating the coverage of blood vessels by vascular smooth muscle cells. To understand the physiologic functions of the two other widely expressed S1P receptors, we generated S1P2 and S1P3 null mice. Neither the S1P2 null mice nor the S1P3 null mice exhibited significant embryonic lethality or obvious phenotypic abnormalities. To unmask possible overlapping or collaborative functions between the S1P1, S1P2, and S1P3 receptors, we examined embryos with multiple S1P receptor mutations. We found that S1P1 S1P2 double null and S1P1 S1P2 S1P3 triple null embryos displayed a substantially more severe vascular phenotype than did embryos with only S1P1 deleted. We also found partial embryonic lethality and vascular abnormalities in S1P2 S1P3 double null embryos. Our results indicate that the S1P1, S1P2 and S1P3 receptors have redundant or cooperative functions for the development of a stable and mature vascular system during embryonic development.

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