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Type: Journal article
Title: Basal and angiopoietin-1-mediated endothelial permeability is regulated by sphingosine kinase-1
Author: Li, X.
Stankovic, M.
Bonder, C.
Hahn, C.
Parsons, M.
Pitson, S.
Xia, P.
Proia, R.
Vadas, M.
Gamble, J.
Citation: Blood, 2008; 111(7):3489-3497
Publisher: Amer Soc Hematology
Issue Date: 2008
ISSN: 0006-4971
Statement of
Xiaochun Li, Milena Stankovic, Claudine S. Bonder, Christopher N. Hahn, Michelle Parsons, Stuart M. Pitson, Pu Xia, Richard L. Proia, Mathew A. Vadas and Jennifer R. Gamble
Abstract: 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.
Keywords: Cells, Cultured
Endothelial Cells
Mice, Knockout
Phosphotransferases (Alcohol Group Acceptor)
Receptors, Lysosphingolipid
RNA, Small Interfering
Amino Acid Substitution
Enzyme Activation
Capillary Permeability
Mutation, Missense
Description: Copyright © 2008 by American Society of Hematology
DOI: 10.1182/blood-2007-05-092148
Appears in Collections:Aurora harvest 5
Molecular and Biomedical Science publications

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