Tissue factor pathway inhibitor (TFPI) interferes with endothelial cell migration by inhibition of both the Erk pathway and focal adhesion proteins

Mathieu Provençal; Marisol Michaud; Édith Beaulieu; David Ratel; Georges-Étienne Rivard; Denis Gingras; Richard Béliveau

doi:10.1160/TH07-10-0623

Thrombosis and Haemostasis, Table of Contents

Thromb Haemost 2008; 99(03): 576-585
DOI: 10.1160/TH07-10-0623

Endothelium and Vascular Development

Schattauer GmbH

Tissue factor pathway inhibitor (TFPI) interferes with endothelial cell migration by inhibition of both the Erk pathway and focal adhesion proteins

Authors

Mathieu Provençal

¹Laboratoire de médecine moléculaire, Hôpital Ste-Justine-UQAM, Centre de cancérologie Charles-Bruneau, Centre de Recherche de l’Hôpital Sainte-Justine, Chemin Côte-Sainte-Catherine, Montréal, Québec, Canada
Marisol Michaud

¹Laboratoire de médecine moléculaire, Hôpital Ste-Justine-UQAM, Centre de cancérologie Charles-Bruneau, Centre de Recherche de l’Hôpital Sainte-Justine, Chemin Côte-Sainte-Catherine, Montréal, Québec, Canada
Édith Beaulieu

¹Laboratoire de médecine moléculaire, Hôpital Ste-Justine-UQAM, Centre de cancérologie Charles-Bruneau, Centre de Recherche de l’Hôpital Sainte-Justine, Chemin Côte-Sainte-Catherine, Montréal, Québec, Canada
David Ratel

¹Laboratoire de médecine moléculaire, Hôpital Ste-Justine-UQAM, Centre de cancérologie Charles-Bruneau, Centre de Recherche de l’Hôpital Sainte-Justine, Chemin Côte-Sainte-Catherine, Montréal, Québec, Canada
Georges-Étienne Rivard

²Service d'Hématologie-Oncologie, Hôpital Ste-Justine, Montréal, Québec, Canada
Denis Gingras

¹Laboratoire de médecine moléculaire, Hôpital Ste-Justine-UQAM, Centre de cancérologie Charles-Bruneau, Centre de Recherche de l’Hôpital Sainte-Justine, Chemin Côte-Sainte-Catherine, Montréal, Québec, Canada
Richard Béliveau

¹Laboratoire de médecine moléculaire, Hôpital Ste-Justine-UQAM, Centre de cancérologie Charles-Bruneau, Centre de Recherche de l’Hôpital Sainte-Justine, Chemin Côte-Sainte-Catherine, Montréal, Québec, Canada

²Service d'Hématologie-Oncologie, Hôpital Ste-Justine, Montréal, Québec, Canada

Abstract

Summary

Tissue factor pathway inhibitor (TFPI) is a plasma Kunitz-type serine protease inhibitor that is mainly known for its inhibition of tissue factor-mediated coagulation. In addition to its anticoagulant properties, emerging data show that TFPI may also regulate endothelial cell functions via a non-haemostatic pathway. In this work we demonstrate that at concentrations within the physiological range,TFPI inhibits both endothelial cell migration and their differentiation into capillary-like structures in vitro. These effects were specific to endothelial cells since no inhibitory effect was observed on the migration of tumor (glio- blastoma) cells. Inhibition of endothelial cell migration was correlated with a concomitant loss in cell adhesion,suggesting an alteration of focal adhesion complex integrity. Accordingly,we observed thatTFPI inhibited the phosphorylation of focal adhesion kinase and paxillin,two key proteins involved in the scaffolding of these complexes, and that this effect was specific to endothelial cells. These results suggest that TFPI influences the angiogenic process via a non-haemostatic pathway, by downregulating the migratory mechanisms of endothelial cells.

Keywords

Angiogenesis - TFPI - endothelial cell migration - focal adhesion complexes - extracellular signal-regulated kinases

Full Text

References

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