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Blood, 15 April 2005, Vol. 105, No. 8, pp. 3178-3184. Prepublished online as a Blood First Edition Paper on December 30, 2004; DOI 10.1182/blood-2004-10-3985. This Article Full Text Full Text (PDF) All Versions of this Article: 2004-10-3985v1 105/8/3178    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 Feistritzer, C. Articles by Riewald, M. Search for Related Content PubMed PubMed Citation Articles by Feistritzer, C. Articles by Riewald, M. Related Collections Signal Transduction Hemostasis, Thrombosis, and Vascular Biology Related Article in Blood Online Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  HEMOSTASIS, THROMBOSIS, AND VASCULAR BIOLOGY Endothelial barrier protection by activated protein C through PAR1-dependent sphingosine 1–phosphate receptor-1 crossactivation Clemens Feistritzer, and Matthias Riewald From the Department of Immunology, The Scripps Research Institute, La Jolla, CA. Endothelial cells normally form a dynamically regulated barrier at the blood-tissue interface, and breakdown of this barrier is a key pathogenic factor in inflammatory disorders such as sepsis. Pro-inflammatory signaling by the blood coagulation protease thrombin through protease activated receptor-1 (PAR1) can disrupt endothelial barrier integrity, whereas the bioactive lipid sphingosine 1-phosphate (S1P) recently has been demonstrated to have potent barrier protective effects. Activated protein C (APC) inhibits thrombin generation and has potent anti-inflammatory effects. Here, we show that APC enhanced endothelial barrier integrity in a dual-chamber system dependent on binding to endothelial protein C receptor, activation of PAR1, and activity of cellular sphingosine kinase. Small interfering RNA that targets sphingosine kinase-1 or S1P receptor-1 blocked this protective signaling by APC. Incubation of cells with PAR1 agonist peptide or low concentrations of thrombin ( 40 pM) had a similar barrier-enhancing effect. These results demonstrate that PAR1 activation on endothelial cells can have opposite biologic effects, reveal a role for cross-communication between the prototypical barrier-protective S1P and barrier-disruptive PAR1 pathway, and suggest that S1P receptor-1 mediates protective effects of APC in systemic inflammation. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? Related Article in Blood Online: APC signaling: tickling PAR1 for barrier protection? Eric Camerer and Shaun R. Coughlin Blood 2005 105: 3004-3005. [Full Text] [PDF] This article has been cited by other articles: X. Li, M. Stankovic, C. S. Bonder, C. N. Hahn, M. Parsons, S. M. Pitson, P. Xia, R. L. Proia, M. A. Vadas, and J. R. Gamble Basal and angiopoietin-1-mediated endothelial permeability is regulated by sphingosine kinase-1 Blood, April 1, 2008; 111(7): 3489 - 3497. [Abstract] [Full Text] [PDF] M. Schouten, W. J. Wiersinga, M. 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