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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 (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 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 Related Article in Blood Online Social Bookmarking                   What's this?  Previous Article  |  Next Article  Submitted October 15, 2004 Accepted December 21, 2004 Endothelial barrier protection by activated protein C through PAR1-dependent sphingosine 1-phosphate receptor-1 crossactivation Clemens Feistritzer and Matthias Riewald* Department of Immunology, The Scripps Research Institute, La Jolla, CA, USA * Corresponding author; email: riewald{at}scripps.edu. 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. Proinflammatory 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) has been recently 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 biological 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? 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