While most cells produce S1P in the intracellular environment as a terminal product of sphingolipid metabolism, vertebrates secrete S1P into the extracellular environment by specific transporters (Proia RL, Hla T. Emerging biology of sphingosine-1-phosphate: its role in pathogenesis and therapy. J Clin Invest. 2015 Apr;125(4):1379-87). Once exported, S1P is solubilized by “chaperones”, which bind, transport and allows activation of cell-surface receptors (Yanagida K, Hla T. Vascular and Immunobiology of the Circulatory Sphingosine 1-Phosphate Gradient. Annu Rev Physiol. 2017 Feb 10;79:67-91.). Lipid phosphate phosphatases and S1P lyase degrades S1P. High levels of S1P in blood and lymph are needed for physiological trafficking of lymphocytes. In the figure below, when red blood cells fail to secrete S1P, blood vessels fragility occurs during embryonic development due to dimimished signaling in the endothelium and hemorrhage and death ensues. We are examining S1P transporters, chaperones and metabolic enzymes in hematopoietic and vascular cells as determinants of S1P gradients that regulate various developmental and physiological processes such as primary vascular network patterning and development of vascular anomalies. Specific organ sites, such as the blood brain barrier, retina, kidney and liver during development, normal physiological conditions and diseases are investigated using genetic mouse models. Our laboratory identified the HDL-bound S1P chaperone, Apolipoprotein M (ApoM). We are examining how ApoM-bound S1P mediates its specific biological actions in vascular and hematopoietic systems. In addition, we are searching for novel S1P chaperones with defined biological functions.