Tissue factor pathway inhibitor (TFPI) interferes with endothelial cell migration by inhibition of both the Erk pathway and focal adhesion proteins
Mathieu Provençal1, Marisol Michaud1, Édith Beaulieu1, David Ratel1, Georges-Étienne Rivard2, Denis Gingras1, Richard Béliveau1,2
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
angiogenesis, TFPI, endothelial cell migration, focal adhesion complexes, extracellular signal-regulated kinases
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 (glioblastoma) 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.