Erythrocyte-derived sphingosine 1-phosphate is essential for vascular development
Yuquan Xiong, … , Richard L. Proia, Timothy Hla
Yuquan Xiong, … , Richard L. Proia, Timothy Hla
Published November 3, 2014; First published September 24, 2014
Citation Information: J Clin Invest. 2014;124(11):4823-4828. https://doi.org/10.1172/JCI77685.
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Brief Report Vascular biology

Erythrocyte-derived sphingosine 1-phosphate is essential for vascular development

Abstract

Transport of oxygen by red blood cells (rbc) is critical for life and embryogenesis. Here, we determined that provision of the lipid mediator sphingosine 1-phosphate (S1P) to the systemic circulation is an essential function of rbc in embryogenesis. Mice with rbc-specific deletion of sphingosine kinases 1 and 2 (Sphk1 and Sphk2) showed embryonic lethality between E11.5 and E12.5 due to defects in vascular development. Administration of an S1P1 receptor agonist to pregnant dams rescued early embryonic lethality. Even though rbc-specific Sphk1 Sphk2–KO embryos were anemic, the erythropoietic capacity of hematopoietic stem cells (HSCs) was not impaired, suggesting that rbc can develop in the absence of sphingosine kinase activity. Indeed, transplantation of HSCs deficient for Sphk1 and Sphk2 into adult mice produced rbc that lacked S1P and attenuated plasma S1P levels in recipients. However, in adult animals, both rbc and endothelium contributed to plasma S1P. Together, these findings demonstrate that rbc are essential for embryogenesis by supplying the lysophospholipid S1P, which regulates embryonic vascular development via its receptors.

Authors

Yuquan Xiong, Peiying Yang, Richard L. Proia, Timothy Hla

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Figure 3

Adult erythropoiesis in the absence of Sphk enzymes.

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Adult erythropoiesis in the absence of Sphk enzymes. (A) Lethally irradi...
(A) Lethally irradiated WT mice were reconstituted with control (Ctl) or RBC Sphk dKO (KO) fetal liver cells. Peripheral blood cell counts for the transplanted mice. HGB, hemoglobin; HCT, hematocrit; MCV, mean corpuscular volume; MCH, mean corpuscular hemoglobin; MCHC, mean corpuscular hemoglobin concentration; RDW-SD, red cell distribution width-standard deviation; RDW-CV, red cell distribution width-coefficient of variation; RET, reticulocytes; PLT, platelets; PDW, platelet distribution width; MPV, mean platelet volume. (B) Eosin staining and transmission electron microscopy images of rbc. Original magnification, ×63 and ×15,000, respectively. Plasma and rbc S1P levels in (C) transplanted mice, (D) WT and Sphk1fl/fl Sphk2+/– Epor-Cre mice, and (E) Sphk1fl/fl Sphk2–/– and EC Sphk dKO mice. n = 3 per group. **P < 0.01. All data represent the mean ± SD.