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(Arteriosclerosis, Thrombosis, and Vascular Biology. 2005;25:976.)
© 2005 American Heart Association, Inc.

Vascular Biology

Sphingosine-1-Phosphate Prevents Tumor Necrosis Factor-–Mediated Monocyte Adhesion to Aortic Endothelium in Mice

David T. Bolick; Suseela Srinivasan; Kyu W. Kim; Melissa E. Hatley; Jeremy J. Clemens; Angela Whetzel; Nicole Ferger; Timothy L. Macdonald; Michael D. Davis; Philip S. Tsao; Kevin R. Lynch; Catherine C. Hedrick

From the Division of Endocrinology & Metabolism and Cardiovascular Research Center (D.T.B., S.S., M.E.H., A.W., N.F., C.C.H.), Department of Chemistry (J.J.C., T.L.M.), Department of Biochemistry & Molecular Genetics (M.D.D.), and Department of Pharmacology (K.W.K., K.R.L., C.C.H.), University of Virginia, Charlottesville, Va; Division of Cardiology (P.S.T.), Stanford University, Palo Alto, Calif.

Correspondence to Catherine C Hedrick, PhD, Cardiovascular Research Center, University of Virginia, 415 Lane Rd, MR5 G123, Charlottesville, VA 22908. E-mail cch6n{at}virginia.edu

Objective— Endothelial activation and monocyte adhesion to endothelium are key events in inflammation. Sphingosine-1-phosphate (S1P) is a sphingolipid that binds to G protein-coupled receptors on endothelial cells (ECs). We examined the role of S1P in modulating endothelial activation and monocyte–EC interactions in vivo.

Methods and Results— We injected C57BL/6J mice intravenously with tumor necrosis factor (TNF)- in the presence and absence of the S1P1 receptor agonist SEW2871 and examined monocyte adhesion. Aortas from TNF-–injected mice had a 4-fold increase in the number of monocytes bound, whereas aortas from TNF- plus SEW2871-treated mice had few monocytes bound (P<0.0001). Using siRNA, we found that inhibiting the S1P1 receptor in vascular ECs blocked the ability of S1P to prevent monocyte–EC interactions in response to TNF-. We examined signaling pathways downstream of S1P1 and found that 100 nM S1P increased phosphorylation of Akt and decreased activation of c-jun.

Conclusions— Thus, we provide the first evidence that S1P signaling through the endothelial S1P1 receptor protects the vasculature against TNF-–mediated monocyte–EC interactions in vivo.

We examined the role of sphingosine-1-phosphate (S1P) in modulating monocyte–endothelial cell (EC) interactions. S1P and a specific S1P1 receptor agonist prevented monocyte adhesion to aorta in tumor necrosis factor (TNF)-–treated mice in vivo. We provide the first evidence to our knowledge that S1P signaling through the endothelial S1P1 receptor protects the vasculature against TNF-–mediated monocyte–EC interactions in vivo.

Key Words: endothelium • sphingosine-1-phosphate • inflammation • Endothelium differentiation gene (Edg) receptors

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