Endogenous EPCR/aPC-PAR1 signaling prevents inflammation-induced vascular leakage and lethality. Blood 2009 Mar 19;113(12):2859-66
Date
01/15/2009Pubmed ID
19141861Pubmed Central ID
PMC2661868DOI
10.1182/blood-2008-12-192385Scopus ID
2-s2.0-63849278353 (requires institutional sign-in at Scopus site) 72 CitationsAbstract
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.
Author List
Niessen F, Furlan-Freguia C, Fernández JA, Mosnier LO, Castellino FJ, Weiler H, Rosen H, Griffin JH, Ruf WAuthor
Hartmut Weiler PhD Associate Professor in the Physiology department at Medical College of WisconsinMESH terms used to index this publication - Major topics in bold
AnimalsCapillary Leak Syndrome
Capillary Permeability
Disseminated Intravascular Coagulation
Endothelial Protein C Receptor
Endothelium, Vascular
Endotoxins
Enzyme Activation
Glycoproteins
Hirudins
Mice
Mice, Inbred C57BL
Mice, Knockout
Nerve Tissue Proteins
Protein C
Receptor, PAR-1
Receptors, Cell Surface
Receptors, Lysosphingolipid
Signal Transduction
Specific Pathogen-Free Organisms
Systemic Inflammatory Response Syndrome
Thiophenes
Thrombin
Thromboplastin
beta-Alanine