Vascular Endothelium As a Contributor of Plasma Sphingosine 1-Phosphate

• Published in: Circulation research Vol. 102; no. 6; pp. 669 - 676
• Main Authors: Venkataraman, Krishnan, Lee, Yong-Moon, Michaud, Jason, Thangada, Shobha, Ai, Youxi, Bonkovsky, Herbert L., Parikh, Nehal S., Habrukowich, Cheryl, Hla, Timothy
• Format: Journal Article
• Language: English
• Published: Hagerstown, MD American Heart Association, Inc 28.03.2008; Lippincott
• Subjects: Adenoviridae - genetics; Aldehyde-Lyases - genetics; Aldehyde-Lyases - metabolism; Anemia - blood; Anemia - chemically induced; Animals; Antibodies, Monoclonal; Biological and medical sciences; Bone Marrow Cells - enzymology; Bone Marrow Cells - metabolism; Bone Marrow Cells - radiation effects; Bone Marrow Transplantation; Cell Line; Cell Line, Tumor; Cells, Cultured; Disease Models, Animal; Endothelial Cells - enzymology; Endothelial Cells - metabolism; Endothelium, Vascular - enzymology; Endothelium, Vascular - metabolism; Fundamental and applied biological sciences. Psychology; Genetic Vectors; Half-Life; Humans; Leukopenia - blood; Liver - enzymology; Liver - metabolism; Lysophospholipids - blood; Lysophospholipids - metabolism; Membrane Proteins - metabolism; Mice; Mice, Inbred C57BL; Mice, Knockout; Phenylhydrazines; Phosphoric Monoester Hydrolases - metabolism; Phosphotransferases (Alcohol Group Acceptor) - deficiency; Phosphotransferases (Alcohol Group Acceptor) - genetics; Phosphotransferases (Alcohol Group Acceptor) - metabolism; Platelet Glycoprotein GPIb-IX Complex - immunology; RNA Interference; RNA, Small Interfering - metabolism; Sphingosine - analogs & derivatives; Sphingosine - blood; Sphingosine - metabolism; Stress, Mechanical; Thrombocytopenia - blood; Thrombocytopenia - immunology; Time Factors; Transduction, Genetic; Vertebrates: cardiovascular system; Whole-Body Irradiation; Phosphates; Gradient; sphingosine 1-phosphate (SIP); sphingosine kinase (Sphk); Enzyme; Transferases; plasma SIP gradient; Endothelium; Vertebrata; Mammalia; Kinase; Shear stress; Circulatory system; SIP lyase (Sgpl)
• ISSN: 0009-7330; 1524-4571; 1524-4571
• DOI: 10.1161/CIRCRESAHA.107.165845

Sphingosine 1-phosphate (S1P), an abundant lipid mediator in plasma, regulates vascular and immune cells by activating S1P receptors. In this report, we investigated the mechanisms by which high plasma S1P levels are maintained in mice. 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). Transplantation of bone marrow from wild-type to Sphk1Sphk2 mice restored plasma S1P levels, suggesting that hematopoietic cells are capable of secreting S1P into plasma. However, plasma S1P levels were not appreciably altered in mice that were thrombocytopenic, anemic, or leukopenic. Surprisingly, reconstitution of Sphk1Sphk2 bone marrow cells into wild-type hosts failed to reduce plasma S1P, suggesting the existence of an additional, nonhematopoietic source for plasma S1P. Adenoviral expression of Sphk1 in the liver of Sphk1 mice restored plasma S1P levels. In vitro, vascular endothelial cells, but not hepatocytes, secreted S1P in a constitutive manner. 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. 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. These data suggest that the vascular endothelium, in addition to the hematopoietic system, is a major contributor of plasma S1P.