Department of Biochemistry, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117596, Singapore.
Université Paris Cité, PARCC, INSERM U970, 56 Rue Leblanc, 75015 Paris, France.
Cell Rep. 2022 Aug 16;40(7):111208. doi: 10.1016/j.celrep.2022.111208.
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.
鞘氨醇-1-磷酸（S1P）是一种有效的脂质介质，由几种细胞类型分泌。我们最近发现，Mfsd2b 是一种来自造血细胞的 S1P 转运蛋白，它贡献了大约 50%的血浆 S1P。在这里，我们报告了 Mfsd2b 和 Spns2 的复合缺失的特征，Spns2 是另一种主要在血管内皮细胞中活跃的 S1P 转运蛋白。Mfsd2b 和 Spns2 的全局缺失（全局双敲除 [gDKO]）导致胚胎在 E14.5 后 14.5 天（E14.5）之前发生胚胎致死，伴有严重的出血，伴随着紧密连接蛋白的缺陷，表明 Mfsd2b 和 Spns2 为信号转导提供 S1P，这对血管完整性至关重要。使用 Mx1Cre（ctDKO-Mx1Cre）对 Mfsd2b 和 Spns2 进行复合出生后缺失导致血浆 S1P 最大减少 80%。ctDKO-Mx1Cre 小鼠对过敏表现出严重的易感性，表明 Mfsd2b 和 Spns2 的 S1P 对血管稳态是必不可少的。我们的结果表明，Mfsd2b 和 Spns2 从 S1P 的输出对于正在发育和成熟的血管系统是必需的。
