Published online 11 February 2009
Haematologica, Vol 94, Issue 3, 387-394 doi:10.3324/haematol.13547
Copyright © 2009 by Ferrata Storti Foundation
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Original Article

Microparticle-associated endothelial protein C receptor and the induction of cytoprotective and anti-inflammatory effects

Margarita Pérez-Casal1, Colin Downey1, Beatriz Cutillas-Moreno1, Mirko Zuzel1, Kenji Fukudome2, Cheng Hock Toh1

1 Division of Haematology, University of Liverpool, UK and
2 Department of Immunology, Saga Medical School, Nabeshima, Japan

Correspondence: Cheng Hock Toh, Department of Haematology, Royal Liverpool University Hospital, Prescot Street, Liverpool L7 8XP, United Kingdom. E-mail:toh{at}liv.ac.uk

Background: The endothelial protein C receptor plays an important role within the protein C pathway in regulating coagulation and inflammation. Recently, we described that endothelial protein C receptor can be released in vitro in microparticulate form from primary endothelial cells by exogenous activated protein C. Activated protein C bound to this endothelial protein C receptor retains anticoagulant activity and we hypothesize that this microparticulate endothelial protein C receptor-activated protein C complex can also cleave endothelial protease-activated receptor 1 to modulate inflammation and increase cell survival. Our main objective was, therefore, to study the effect that microparticle-associated endothelial protein C receptor-activated protein C has on endothelial function.

Design and Methods: Mini-arrays were used and probed with cDNA obtained from endothelial cells after treatment with microparticle-associated endothelial protein C receptor-activated protein C and results were confirmed by real time polymerase chain reaction. The functional relevance of changes at gene level were further analyzed by endothelial apoptosis and permeability assays, in the presence and absence of specific blockade of endothelial protein C receptor, protein C and protease-activated receptor 1.

Results: Gene profiling of endothelial cells stimulated by 40 nmol/L activated protein C on microparticles showed significant changes in anti-apoptotic and inflammatory pathways. This was accompanied by protease-activated receptor 1-dependent anti-apoptotic and barrier protective effects, the latter of which also involved sphingosine 1-phosphate receptor and vascular endothelial growth factor receptor-2/ kinase insert domain receptor. Protein C blockade reversed these effects showing specificity for activated protein C on microparticles. Furthermore, confocal microscopy and enzyme-linked immunosorbent assay of plasma obtained from septic patients during recombinant activated protein C treatment showed evidence of their presence in vivo.

Conclusions: Activated protein C on microparticle-associated endothelial protein C receptor release can induce protease-activated receptor 1-dependent endothelial effects. The mechanisms underlying barrier protection involve sphingosine 1-phosphate receptor and kinase insert domain receptor.

Key words: activated protein C, endothelial protein C receptor, microparticles, protease activated receptor, vascular endothelial growth factor receptor-2.


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O. Morel, F. Toti, N. Morel, and J.-M. Freyssinet
Microparticles in endothelial cell and vascular homeostasis: are they really noxious?
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