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

Area of Science:

• Hematology
• Developmental Biology
• Lipid Metabolism

Background:

• Red blood cells (RBCs) are crucial for oxygen transport, essential for life and embryonic development.
• The lipid mediator sphingosine 1-phosphate (S1P) plays significant roles in various physiological processes.
• The specific contribution of RBCs to circulating S1P levels and its role in embryogenesis remains to be fully elucidated.

Purpose of the Study:

• To investigate the essential function of RBCs in providing sphingosine 1-phosphate (S1P) during embryogenesis.
• To determine the impact of impaired sphingosine kinase activity in RBCs on embryonic development and vascular formation.
• To explore the compensatory mechanisms and contributions of other tissues to plasma S1P levels in adult animals.

Main Methods:

• Generation of RBC-specific knockout mice lacking sphingosine kinases 1 and 2 (Sphk1 and Sphk2).
• Administration of an S1P1 receptor agonist to rescue embryonic lethality in knockout models.
• Hematopoietic stem cell (HSC) transplantation experiments in adult mice to assess RBC S1P production and plasma S1P levels.
• Analysis of embryonic vascular development and erythropoiesis in knockout embryos.

Main Results:

• RBC-specific deletion of Sphk1 and Sphk2 led to embryonic lethality between E11.5 and E12.5, characterized by vascular development defects.
• Administration of an S1P1 receptor agonist rescued the embryonic lethality.
• Despite anemia, the erythropoietic capacity of HSCs was not impaired in knockout embryos.
• Transplantation of Sphk1/Sphk2-deficient HSCs resulted in RBCs lacking S1P and reduced plasma S1P levels in adult recipients.
• In adult animals, both RBCs and the endothelium contribute to plasma S1P levels.

Conclusions:

• RBCs are essential for embryogenesis through the provision of sphingosine 1-phosphate (S1P) to the systemic circulation.
• S1P supplied by RBCs is critical for regulating embryonic vascular development via S1P receptors.
• While RBCs are a key source of S1P during embryogenesis, both RBCs and endothelium contribute to plasma S1P in adult animals.