Abstract
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 S1P(1) 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 S1P(2) and S1P(3) null mice. Neither the S1P(2) null mice nor the S1P(3) null mice exhibited significant embryonic lethality or obvious phenotypic abnormalities. To unmask possible overlapping or collaborative functions between the S1P(1), S1P(2), and S1P(3) receptors, we examined embryos with multiple S1P receptor mutations. We found that S1P(1) S1P(2) double null and S1P(1) S1P(2) S1P(3) triple null embryos displayed a substantially more severe vascular phenotype than did embryos with only S1P(1) deleted. We also found partial embryonic lethality and vascular abnormalities in S1P(2) S1P(3) double null embryos. Our results indicate that the S1P(1), S1P(2) and S1P(3) receptors have redundant or cooperative functions for the development of a stable and mature vascular system during embryonic development.
Highlights
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
The vasculature develops through the sequential processes of vasculogenesis and angiogenesis [33,34,35]
Beginning at around E8.5 in the mouse, vasculogenesis includes the differentiation of endothelial cells, their migration and proliferation, and the formation of the primitive vascular plexus
Summary
We found partial embryonic lethality and vascular abnormalities in S1P2 S1P3 double null embryos. Generation of S1P2 and S1P3 Receptor Null Mice—The S1P2 and S1P3 genes were each targeted by homologous recombination in TC1 ES cells (Fig. 1). In the targeted S1P2 ES cell line, the wild-type S1P2 allele and the recombined S1P2 allele were detected by Southern blot analysis as 12-kb and 7.5-kb bands, FIG.
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