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

Thromb Haemost. 2008 Mar;99(3):576-85. doi: 10.1160/TH07-10-0623.

Abstract

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 that TFPI 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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Angiogenic Proteins / isolation & purification
  • Angiogenic Proteins / metabolism*
  • Angiogenic Proteins / pharmacology
  • Cell Adhesion
  • Cell Differentiation
  • Cell Line, Tumor
  • Cell Movement* / drug effects
  • Cell Shape
  • Cells, Cultured
  • Cloning, Molecular
  • Dose-Response Relationship, Drug
  • Endothelial Cells / drug effects
  • Endothelial Cells / enzymology
  • Endothelial Cells / metabolism*
  • Extracellular Signal-Regulated MAP Kinases / antagonists & inhibitors
  • Extracellular Signal-Regulated MAP Kinases / metabolism*
  • Focal Adhesion Protein-Tyrosine Kinases / antagonists & inhibitors
  • Focal Adhesion Protein-Tyrosine Kinases / metabolism*
  • Humans
  • Lipoproteins / isolation & purification
  • Lipoproteins / metabolism*
  • Lipoproteins / pharmacology
  • Lysophospholipids / metabolism
  • Mitogen-Activated Protein Kinase 1 / metabolism
  • Mitogen-Activated Protein Kinase 3 / metabolism
  • Neovascularization, Physiologic* / drug effects
  • Paxillin / metabolism*
  • Phosphorylation
  • Recombinant Proteins / metabolism
  • Sphingosine / analogs & derivatives
  • Sphingosine / metabolism

Substances

  • Angiogenic Proteins
  • Lipoproteins
  • Lysophospholipids
  • PXN protein, human
  • Paxillin
  • Recombinant Proteins
  • lipoprotein-associated coagulation inhibitor
  • sphingosine 1-phosphate
  • Focal Adhesion Protein-Tyrosine Kinases
  • Extracellular Signal-Regulated MAP Kinases
  • Mitogen-Activated Protein Kinase 1
  • Mitogen-Activated Protein Kinase 3
  • Sphingosine