title: Endothelial cell protein C receptor-mediated redistribution and tissue-level accumulation of factor VIIa.
abstract: BACKGROUND
  Recent studies show that activated factor VII (FVIIa) binds to the endothelial cell protein C receptor (EPCR) on the vascular endothelium; however, the importance of this interaction in hemostasis or pathophysiology is unknown.
  
  
  OBJECTIVE
  The aim of the present study was to investigate the role of the FVIIa interaction with EPCR on the endothelium in mediating FVIIa transport from the circulation to extravascular tissues.
  
  
  METHODS
  Wild-type, EPCR-deficient or ECPR-over-expressing mice were injected with human recombinant (r)FVIIa (120 μg kg(-1) body weight) via the tail vein. At varying time intervals after rFVIIa administration, blood and various tissues were collected to measure FVIIa antigen and activity levels. Tissue sections were analyzed by immunohistochemistry for FVIIa and EPCR.
  
  
  RESULTS
  The data reveal that, after intravenous (i.v.) injection, rFVIIa rapidly disappears from the blood and associates with the endothelium in an EPCR-dependent manner. Immunohistochemical analyses revealed that the association of FVIIa with the endothelium was maximal at 30 min and thereafter progressively declined. The FVIIa association with the endothelium was undetectable at time points exceeding 24 h post-FVIIa administration. The levels of rFVIIa accumulated in tissue correlate with expression levels of EPCR in mice and FVIIa associated with tissues remained functionally active for periods of at least 7 days.
  
  
  CONCLUSIONS
  The observation that an EPCR-dependent association of FVIIa with the endothelium is most pronounced soon after rFVIIa administration and subsequently declines temporally, combined with the retention of functionally active FVIIa in tissue homogenates for extended periods, indicates that FVIIa binding to EPCR on the endothelium facilitates the transport of FVIIa from circulation to extravascular tissues where TF resides.
authors.affiliation: Department of Cellular and Molecular Biology, Center for Biomedical Research, The University of Texas Health Science Center at Tyler, Tyler, TX, USA Department of Medicine, Malmö University Hospital, University of Lund, Malmö, Sweden Cardiovascular Biology Research Program, Oklahoma Medical Research Foundation, Howard Hughes Medical Institute, Oklahoma City, OK, USA.
authors.forename: C A
authors.initials: CA
authors.lastname: Clark
authors.forename: R
authors.initials: R
authors.lastname: Vatsyayan
authors.forename: U
authors.initials: U
authors.lastname: Hedner
authors.forename: C T
authors.initials: CT
authors.lastname: Esmon
authors.forename: U R
authors.initials: UR
authors.lastname: Pendurthi
authors.forename: L V M
authors.initials: LV
authors.lastname: Rao
mesh_terms: D000818:Animals; D001692:Biological Transport; D001779:Blood Coagulation Factors / Q000378:metabolism*; D042783:Endothelial Cells / Q000166:cytology*; D000074283:Endothelial Protein C Receptor; D004730:Endothelium, Vascular / Q000378:metabolism; D015942:Factor VIIa / Q000737:chemistry*; D006467:Hemophilia A / Q000378:metabolism; D006487:Hemostasis; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D011485:Protein Binding; D011956:Receptors, Cell Surface / Q000235:genetics* / Q000378:metabolism*; D011994:Recombinant Proteins / Q000097:blood / Q000737:chemistry / Q000378:metabolism; D015398:Signal Transduction; D013925:Thromboplastin / Q000378:metabolism*; D013997:Time Factors; D014018:Tissue Distribution
chemical_list: D001779:Blood Coagulation Factors; D000074283:Endothelial Protein C Receptor; C080248:Procr protein, mouse; D011956:Receptors, Cell Surface; D011994:Recombinant Proteins; C091963:activated protein C receptor; D013925:Thromboplastin; C103587:recombinant FVIIa; D015942:Factor VIIa