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Factor VIIa binding to endothelial cell protein C receptor: Differences between mouse and human systems

Sen, Prosenjit; Clark, Curtis A.; Gopalakrishnan, Ramakrishnan; Hedner, Ulla LU ; Esmon, Charles T.; Pendurthi, Usha R. and Rao, L. Vijaya Mohan (2012) In Thrombosis and Haemostasis 107(5). p.951-961
Abstract
Recent in vitro studies have shown that the zymogen and activated form of factor (F)VII bind to endothelial cell protein C receptor (EPCR). At present, there is no evidence that FVIIa binds to EPCR on vascular endothelium in vivo in the presence of circulating protein C, a primary ligand for EPCR. The present study was carried out to investigate the interaction of murine and human ligands with murine EPCR both in vivo and in vitro. Measurement of endogenous plasma levels of FVII in wild-type, EPCR-deficient and EPCR-over expressing mice showed slightly lower levels of FVII in EPCR-over expressing mice. However, infusion of high concentrations of competing ligands, either human APCi or FVIIai, to EPCR-over expressing mice failed to increase... (More)
Recent in vitro studies have shown that the zymogen and activated form of factor (F)VII bind to endothelial cell protein C receptor (EPCR). At present, there is no evidence that FVIIa binds to EPCR on vascular endothelium in vivo in the presence of circulating protein C, a primary ligand for EPCR. The present study was carried out to investigate the interaction of murine and human ligands with murine EPCR both in vivo and in vitro. Measurement of endogenous plasma levels of FVII in wild-type, EPCR-deficient and EPCR-over expressing mice showed slightly lower levels of FVII in EPCR-over expressing mice. However, infusion of high concentrations of competing ligands, either human APCi or FVIIai, to EPCR-over expressing mice failed to increase plasma levels of mouse FVII whereas they increased the plasma levels of protein C by two- to three-fold. Examining the association of exogenously administered mouse FVIIa or human FVIIa by immunohistochemistry revealed that human, but not murine FVIIa, binds to the murine endothelium in an EPCR-dependent manner. vitro binding studies performed using surface plasmon resonance and endothelial cells revealed that murine FVIIa binds murine EPCR negligibly. Human FVIIa binding to EPCR, particularly to mouse EPCR, is markedly enhanced by availability of Mg2+ ions. In summary, our data show that murine FVIIa binds poorly to murine EPCR, whereas human FVIIa binds efficiently to both murine and human EPCR. Our data suggest that one should consider the use of human FVIIa in mouse models to investigate the significance of FVIIa and EPCR interaction. (Less)
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author
organization
publishing date
type
Contribution to journal
publication status
published
subject
keywords
Endothelial cell protein C receptor, factor VIIa, protein C
in
Thrombosis and Haemostasis
volume
107
issue
5
pages
951 - 961
publisher
F K Schattauer Verlag Gmbh
external identifiers
  • wos:000304638400017
  • scopus:84860449128
ISSN
0340-6245
DOI
10.1160/TH11-09-0672
language
English
LU publication?
yes
id
310f6818-e4b4-49b7-9761-a6d6c913e709 (old id 2911678)
date added to LUP
2012-08-01 09:47:34
date last changed
2017-09-24 03:52:53
@article{310f6818-e4b4-49b7-9761-a6d6c913e709,
  abstract     = {Recent in vitro studies have shown that the zymogen and activated form of factor (F)VII bind to endothelial cell protein C receptor (EPCR). At present, there is no evidence that FVIIa binds to EPCR on vascular endothelium in vivo in the presence of circulating protein C, a primary ligand for EPCR. The present study was carried out to investigate the interaction of murine and human ligands with murine EPCR both in vivo and in vitro. Measurement of endogenous plasma levels of FVII in wild-type, EPCR-deficient and EPCR-over expressing mice showed slightly lower levels of FVII in EPCR-over expressing mice. However, infusion of high concentrations of competing ligands, either human APCi or FVIIai, to EPCR-over expressing mice failed to increase plasma levels of mouse FVII whereas they increased the plasma levels of protein C by two- to three-fold. Examining the association of exogenously administered mouse FVIIa or human FVIIa by immunohistochemistry revealed that human, but not murine FVIIa, binds to the murine endothelium in an EPCR-dependent manner. vitro binding studies performed using surface plasmon resonance and endothelial cells revealed that murine FVIIa binds murine EPCR negligibly. Human FVIIa binding to EPCR, particularly to mouse EPCR, is markedly enhanced by availability of Mg2+ ions. In summary, our data show that murine FVIIa binds poorly to murine EPCR, whereas human FVIIa binds efficiently to both murine and human EPCR. Our data suggest that one should consider the use of human FVIIa in mouse models to investigate the significance of FVIIa and EPCR interaction.},
  author       = {Sen, Prosenjit and Clark, Curtis A. and Gopalakrishnan, Ramakrishnan and Hedner, Ulla and Esmon, Charles T. and Pendurthi, Usha R. and Rao, L. Vijaya Mohan},
  issn         = {0340-6245},
  keyword      = {Endothelial cell protein C receptor,factor VIIa,protein C},
  language     = {eng},
  number       = {5},
  pages        = {951--961},
  publisher    = {F K Schattauer Verlag Gmbh},
  series       = {Thrombosis and Haemostasis},
  title        = {Factor VIIa binding to endothelial cell protein C receptor: Differences between mouse and human systems},
  url          = {http://dx.doi.org/10.1160/TH11-09-0672},
  volume       = {107},
  year         = {2012},
}