Mfsd2b and Spns2 are essential for maintenance of blood vessels during development and in anaphylactic shock

Sphingosine-1-phosphate (S1P) is a potent lipid mediator that is secreted by several cell types. We recently showed that Mfsd2b is an S1P transporter from hematopoietic cells that contributes approximately 50% plasma S1P. Here we report the characterization of compound deletion of Mfsd2b and Spns2, another S1P transporter active primarily in endothelial cells. Global deletion of Mfsd2b and Spns2 (global double knockout [gDKO]) results in embryonic lethality beyond embryonic day 14.5 (E14.5), with severe hemorrhage accompanied by defects of tight junction proteins, indicating that Mfsd2b and Spns2 provide S1P for signaling, which is essential for blood vessel integrity. Compound postnatal deletion of Mfsd2b and Spns2 using Mx1Cre (ctDKO-Mx1Cre) results in maximal 80% reduction of plasma S1P. ctDKO-Mx1Cre mice exhibit severe susceptibility to anaphylaxis, indicating that S1P from Mfsd2b and Spns2 is indispensable for vascular homeostasis. Our results show that S1P export from Mfsd2b and Spns2 is essential for developing and mature vasculature. [Display omitted] •Global deletion of Mfsd2b and Spns2 causes embryonic lethality•Mfsd2b and Spns2 in Mx1Cre-sensitive cells provide 80% of the plasma S1P•20% of the plasma S1P in Mx1Cre-sensitive cells is independent of these transporters•Plasma S1P is essential for maintenance of vascular integrity and vascular tone Sphingosine-1-phosphate (S1P) is a potent lipid mediator. Using mouse models, Le et al. demonstrate that the sources of extracellular S1P released from Mfsd2b and Spns2 are essential for protection of the vasculature from hemorrhages during development and in anaphylactic shock.