Factor VIIa bound to endothelial cell protein C receptor activates protease activated receptor-1 and mediates cell signaling and barrier protection.
Recent studies have shown that factor VIIa (FVIIa) binds to the endothelial cell protein C receptor (EPCR), a cellular receptor for protein C and activated protein C, but the physiologic significance of this interaction is unclear. In the present study, we show that FVIIa, upon binding to EPCR on endothelial cells, activates endogenous protease activated receptor-1 (PAR1) and induces PAR1-mediated p44/42 mitogen-activated protein kinase (MAPK) activation. Pretreatment of endothelial cells with FVIIa protected against thrombin-induced barrier disruption. This FVIIa-induced, barrier-protective effect was EPCR dependent and did not involve PAR2. Pretreatment of confluent endothelial monolayers with FVIIa before thrombin reduced the development of thrombin-induced transcellular actin stress fibers, cellular contractions, and paracellular gap formation. FVIIa-induced p44/42 MAPK activation and the barrier-protective effect are mediated via Rac1 activation. Consistent with in vitro findings, in vivo studies using mice showed that administration of FVIIa before lipopolysaccharide (LPS) treatment attenuated LPS-induced vascular leakage in the lung and kidney. Overall, our present data provide evidence that FVIIa bound to EPCR on endothelial cells activates PAR1-mediated cell signaling and provides a barrier-protective effect. These findings are novel and of great clinical significance, because FVIIa is used clinically for the prevention of bleeding in hemophilia and other bleeding disorders.
Center for Biomedical Research, The University of Texas Health Science Center at Tyler, Tyler, TX, USA.
Prosenjit
P
Sen
Ramakrishnan
R
Gopalakrishnan
Hema
H
Kothari
Shiva
S
Keshava
Curtis A
CA
Clark
Charles T
CT
Esmon
Usha R
UR
Pendurthi
L Vijaya Mohan
LV
Rao
D000818:Animals; D015703:Antigens, CD / Q000378:metabolism*; D002199:Capillary Permeability / Q000187:drug effects; D003599:Cytoskeleton / Q000187:drug effects / Q000378:metabolism; D042783:Endothelial Cells / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism*; D000074283:Endothelial Protein C Receptor; D004789:Enzyme Activation / Q000187:drug effects; D015942:Factor VIIa / Q000008:administration & dosage / Q000378:metabolism* / Q000494:pharmacology; D006801:Humans; D008070:Lipopolysaccharides / Q000494:pharmacology; D051379:Mice; D008810:Mice, Inbred C57BL; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D011485:Protein Binding / Q000187:drug effects; D044463:Receptor, PAR-1 / Q000378:metabolism*; D011956:Receptors, Cell Surface / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D013917:Thrombin / Q000494:pharmacology; D020830:rac1 GTP-Binding Protein / Q000378:metabolism; D020741:rho GTP-Binding Proteins / Q000378:metabolism
D015703:Antigens, CD; D000074283:Endothelial Protein C Receptor; D008070:Lipopolysaccharides; C478370:PROCR protein, human; D044463:Receptor, PAR-1; D011956:Receptors, Cell Surface; D048052:Mitogen-Activated Protein Kinase 3; D015942:Factor VIIa; D013917:Thrombin; D020830:rac1 GTP-Binding Protein; D020741:rho GTP-Binding Proteins
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