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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.
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Submitted December 2, 2008
Accepted January 6, 2009
Endogenous EPCR/aPC-PAR1 signaling prevents inflammation-induced vascular leakage and lethality
Frank Niessen, Christian Furlan-Freguia, Jose A. Fernandez, Laurent O. Mosnier, Francis J. Castellino, Hartmut Weiler, Hugh Rosen, John H. Griffin, and Wolfram Ruf*
Department of Immunology and Microbial Science, The Scripps Research Institute, La Jolla, CA, United States
Department of Molecular and Experimental Medicine, The Scripps Research Institute, La Jolla, CA, United States
University of Notre Dame, Notre Dame, IN, United States
Blood Center of Wisconsin, Milwaukee, WI, United States
Department of Chemical Physiology, The Scripps Research Institute, La Jolla, CA, United States
* Corresponding author; email: ruf{at}scripps.edu.
Protease activated receptor (PAR) 1 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 define further 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.
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