![]() In this report, we show that the vascular system, in addition to the hematopoietic system, is important for the maintenance of high plasma S1P levels. 8,12 However, the existence of additional sources of S1P was postulated. 10,20 However, 2 recent studies have suggested that red blood cells (RBCs) and other hematopoietic cells are major cellular sources of plasma S1P. The cellular source(s) of plasma S1P was widely assumed to be from the platelets. 15,17,18 High Sphk1 activity is present in blood, and Sphk1 −/− plasma contains significantly attenuated S1P levels. Recent studies have shown that Sphk1 activity is an important factor in determining plasma S1P levels. 16 The concentration of S1P in the cell is determined by the activity of biosynthetic enzymes (sphingosine kinase -1 and -2) and the degradative enzymes (S1P lyase and S1P phosphatase -1 and -2). Secretion of S1P is observed in a variety of cells including platelets, 9–11 erythrocytes, 9,12,13 mononuclear cells, neutrophils, 9 mast cells, 14,15 and endothelial cells. The regulation of S1P production and release is not well understood. This concentration difference of S1P between plasma and tissues has been termed the vascular S1P gradient, which was shown to be functionally important in lymphocyte egress from the lymphoid tissues and the thymus. In contrast, S1P levels in tissues are considerably lower (0.5 to 75 pmol/mg wet weight), although tissues with high blood content, such as spleen, are exceptions. 5,6 Thus, S1P receptors on blood-borne cells are likely to be constitutively activated. S1P is abundant (0.1 to 1.2 μmol/L) in plasma, where it is mainly bound to albumin and high-density lipoprotein (HDL). Intracellular signaling of these receptors are thought to mediate most of the effects of S1P. S1P binds to and activates a widely expressed family of G protein–coupled receptors, termed S1PRs. The bioactive lipid sphingosine 1-phosphate (S1P) is a potent regulator of numerous biological responses, the most well characterized being cardiovascular and immune effects. These data suggest that the vascular endothelium, in addition to the hematopoietic system, is a major contributor of plasma S1P. Modulation of expression of endothelial S1P lyase with small interfering RNA and adenoviral expression altered S1P secretion, suggesting an important role played by this enzyme. Interestingly, laminar shear stress downregulated the expression of S1P lyase ( Sgpl) and S1P phosphatase-1 ( Sgpp1) while concomitantly stimulating S1P release from endothelial cells in vitro. In vitro, vascular endothelial cells, but not hepatocytes, secreted S1P in a constitutive manner. Adenoviral expression of Sphk1 in the liver of Sphk1 −/− mice restored plasma S1P levels. Surprisingly, reconstitution of Sphk1 −/− Sphk2 +/− bone marrow cells into wild-type hosts failed to reduce plasma S1P, suggesting the existence of an additional, nonhematopoietic source for plasma S1P. However, plasma S1P levels were not appreciably altered in mice that were thrombocytopenic, anemic, or leukopenic. Transplantation of bone marrow from wild-type to Sphk1 −/− Sphk2 +/− mice restored plasma S1P levels, suggesting that hematopoietic cells are capable of secreting S1P into plasma. We found that plasma S1P turns over rapidly with a half-life of ≈15 minutes, suggesting the existence of a high-capacity biosynthetic source(s). In this report, we investigated the mechanisms by which high plasma S1P levels are maintained in mice. Sphingosine 1-phosphate (S1P), an abundant lipid mediator in plasma, regulates vascular and immune cells by activating S1P receptors. Customer Service and Ordering Information.Stroke: Vascular and Interventional Neurology.Journal of the American Heart Association (JAHA).Circ: Cardiovascular Quality & Outcomes.Arteriosclerosis, Thrombosis, and Vascular Biology (ATVB).
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