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Blood, 1 April 2008, Vol. 111, No. 7, pp. 3489-3497. Prepublished online as a Blood First Edition Paper on January 16, 2008; DOI 10.1182/blood-2007-05-092148. This Article Full Text Full Text (PDF) Supplemental Methods and Figures All Versions of this Article: blood-2007-05-092148v1 111/7/3489    most recent Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Rights and Permissions Citing Articles Citing Articles via HighWire Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Li, X. Articles by Gamble, J. R. Search for Related Content PubMed PubMed Citation Articles by Li, X. Articles by Gamble, J. R. Related Collections Hemostasis, Thrombosis, and Vascular Biology Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  HEMOSTASIS, THROMBOSIS, AND VASCULAR BIOLOGY Basal and angiopoietin-1–mediated endothelial permeability is regulated by sphingosine kinase-1 Xiaochun Li1, Milena Stankovic1, Claudine S. Bonder1, Christopher N. Hahn1, Michelle Parsons1, Stuart M. Pitson1, Pu Xia2, Richard L. Proia3, Mathew A. Vadas2, and Jennifer R. Gamble2 1 Division of Human Immunology, Hanson Institute, Institute of Medical & Veterinary Science, Adelaide, Australia; 2 Centenary Institute of Cancer Medicine and Cell Biology, Medical Foundation and the University of Sydney, Sydney, Australia; and 3 Genetics of Development and Disease Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD Endothelial cells (ECs) regulate the barrier function of blood vessels. Here we show that basal and angiopoietin-1 (Ang-1)–regulated control of EC permeability is mediated by 2 different functional states of sphingosine kinase-1 (SK-1). Mice depleted of SK-1 have increased vascular leakiness, whereas mice transgenic for SK-1 in ECs show attenuation of leakiness. Furthermore, Ang-1 rapidly and transiently stimulates SK-1 activity and phosphorylation, and induces an increase in intracellular sphingosine-1-phosphate (S1P) concentration. Overexpression of SK-1 resulted in inhibition of permeability similar to that seen for Ang-1, whereas knockdown of SK-1 by small interfering RNA blocked Ang-1-mediated inhibition of permeability. Transfection with SKS225A, a nonphosphorylatable mutant of SK-1, inhibited basal leakiness, and both SKS225A and a dominant-negative SK-1 mutant removed the capacity of Ang-1 to inhibit permeability. These effects were independent of extracellular S1P as knockdown or inhibition of S1P1, S1P2, or S1P3, did not affect the Ang-1 response. Thus, SK-1 levels in ECs powerfully regulate basal permeability in vitro and in vivo. In addition, the Ang-1–induced inhibition of leakiness is mediated through activation of SK-1, defining a new signaling pathway in the Ang-1 regulation of permeability. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? This article has been cited by other articles: J.-J. Liao, M.-C. Huang, K. Fast, K. Gundling, M. Yadav, J. R. Van Brocklyn, M. R. Wabl, and E. J. Goetzl Immunosuppressive human anti-lymphocyte autoantibodies specific for the type 1 sphingosine 1-phosphate receptor FASEB J, June 1, 2009; 23(6): 1786 - 1796. [Abstract] [Full Text] [PDF] J. S. Karliner Sphingosine kinase regulation and cardioprotection Cardiovasc Res, May 1, 2009; 82(2): 184 - 192. [Abstract] [Full Text] [PDF] F. Niessen, C. Furlan-Freguia, J. A. Fernandez, L. O. Mosnier, F. J. Castellino, H. Weiler, H. Rosen, J. H. Griffin, and W. Ruf Endogenous EPCR/aPC-PAR1 signaling prevents inflammation-induced vascular leakage and lethality Blood, March 19, 2009; 113(12): 2859 - 2866. [Abstract] [Full Text] [PDF] C. S. Bonder, W. Y. Sun, T. Matthews, C. Cassano, X. Li, H. S. Ramshaw, S. M. Pitson, A. F. Lopez, P. T. Coates, R. L. Proia, et al. Sphingosine kinase regulates the rate of endothelial progenitor cell differentiation Blood, February 26, 2009; 113(9): 2108 - 2117. [Abstract] [Full Text] [PDF]

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