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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 |
Published version: | http://dx.doi.org/10.1182/blood-2007-05-092148 |
Appears in Collections: | Aurora harvest 5 Molecular and Biomedical Science publications |
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