Please use this identifier to cite or link to this item: https://hdl.handle.net/2440/53723
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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
1528-0020
Statement of
Responsibility: 
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
Animals
Mice, Knockout
Humans
Mice
Sphingosine
Phosphotransferases (Alcohol Group Acceptor)
Lysophospholipids
Angiopoietin-1
Receptors, Lysosphingolipid
RNA, Small Interfering
Transfection
Amino Acid Substitution
Enzyme Activation
Capillary Permeability
Phosphorylation
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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