SEARCH:   Advanced

Blood, 19 March 2009, Vol. 113, No. 12, pp. 2859-2866. Prepublished online as a Blood First Edition Paper on January 13, 2009; DOI 10.1182/blood-2008-12-192385. This Article Full Text Full Text (PDF) All Versions of this Article: blood-2008-12-192385v1 113/12/2859    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 Niessen, F. Articles by Ruf, W. Search for Related Content PubMed PubMed Citation Articles by Niessen, F. Articles by Ruf, W. Related Collections Thrombosis and Hemostasis Vascular Biology Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  VASCULAR BIOLOGY Endogenous EPCR/aPC-PAR1 signaling prevents inflammation-induced vascular leakage and lethality Frank Niessen1,*, Christian Furlan-Freguia1,*, José A. Fernández2, Laurent O. Mosnier2, Francis J. Castellino3, Hartmut Weiler4, Hugh Rosen1,5, John H. Griffin2, and Wolfram Ruf1 Departments of 1 Immunology and Microbial Science, and 2 Molecular and Experimental Medicine, The Scripps Research Institute, La Jolla, CA; 3 University of Notre Dame, IN; 4 Blood Center of Wisconsin, Milwaukee; and 5 Department of Chemical Physiology, The Scripps Research Institute, La Jolla, CA Protease activated receptor 1 (PAR1) signaling can play opposing roles in sepsis, either promoting dendritic cell (DC)–dependent coagulation and inflammation or reducing sepsis lethality due to activated protein C (aPC) therapy. To further define this PAR1 paradox, we focused on the vascular effects of PAR1 signaling. Pharmacological perturbations of the intravascular coagulant balance were combined with genetic mouse models to dissect the roles of endogenously generated thrombin and aPC during escalating systemic inflammation. Acute blockade of the aPC pathway with a potent inhibitory antibody revealed that thrombin-PAR1 signaling increases inflammation-induced vascular hyperpermeability. Conversely, aPC-PAR1 signaling and the endothelial cell PC receptor (EPCR) prevented vascular leakage, and pharmacologic or genetic blockade of this pathway sensitized mice to LPS-induced lethality. Signaling-selective aPC variants rescued mice with defective PC activation from vascular leakage and lethality. Defects in the aPC pathway were fully compensated by sphingosine 1 phosphate receptor 3 (S1P3) deficiency or by selective agonists of the S1P receptor 1 (S1P1), indicating that PAR1 signaling contributes to setting the tone for the vascular S1P1/S1P3 balance. Thus, the activating proteases and selectivity in coupling to S1P receptor subtypes determine vascular PAR1 signaling specificity in systemic inflammatory response syndromes in vivo. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? This article has been cited by other articles: M. Delvaeye and E. M. Conway Coagulation and innate immune responses: can we view them separately? Blood, September 17, 2009; 114(12): 2367 - 2374. [Abstract] [Full Text] [PDF] G. L. Van Sluis, T. M.H. Niers, C. T. Esmon, W. Tigchelaar, D. J. Richel, H. R. Buller, C. J.F. Van Noorden, and C. A. Spek Endogenous activated protein C limits cancer cell extravasation through sphingosine-1-phosphate receptor 1-mediated vascular endothelial barrier enhancement Blood, August 27, 2009; 114(9): 1968 - 1973. [Abstract] [Full Text] [PDF] E. G. Brooks, W. Trotman, M. P. Wadsworth, D. J. Taatjes, M. F. Evans, F. P. Ittleman, P. W. Callas, C. T. Esmon, and E. G. Bovill Valves of the deep venous system: an overlooked risk factor Blood, August 6, 2009; 114(6): 1276 - 1279. [Abstract] [Full Text] [PDF]

	Copyright © 2009 by American Society of Hematology         Online ISSN: 1528-0020