Fibrinogen interactions with ICAM-1 (CD54) regulate endothelial cell survival

Eur J Biochem. 2000 Aug;267(15):4693-704. doi: 10.1046/j.1432-1327.2000.01520.x.


We tested hypothesis that the interaction of fibrinogen (Fg) with intercellular adhesion molecule 1 (ICAM-1) mediates cellular adhesion and cell proliferation. Our results demonstrate that Fg : ICAM-1 ligation mediates endothelial cell survival and has an anti-apoptotic effect via activation of the MAP kinase pathway. Fg : ICAM-1 ligation in endothelial cells treated with tumor necrosis factor (TNF)alpha resulted in the hyperphosphorylation of extracellular signal-regulated kinase (ERK)-1/2 (eightfold to 10-fold) at 5-30 min. The specificity of ERK-1/2 phosphorylation was verified using the recognition peptides Fg-gamma-(117-133) and ICAM-1(8-22). ERK-1/2 hyperphosphorylation was dependent on intact cytoskeleton, as treatment with cytochalasin B and nocodazole blocked this activity. The attachment of TNFalpha-treated endothelial cells to fibrinogen or Fg-gamma-(117-133) resulted in cell survival, as assessed by an annexin V binding assay. ICAM-1(8-22) blocked the survival process. The MEK-1 inhibitor PD 98059 blocked ERK-1/2 phosphorylation, and treatment of endothelial cells with PD 98059 resulted in apoptosis even upon Fg : ICAM-1 ligation. Cells transfected with dominant-negative ERK-1/2 underwent apoptosis upon Fg : ICAM-1 ligation. Cell survival factor A1 was specifically upregulated upon adhesion of TNFalpha-stimulated endothelial cells to Fg. A1 expression was blocked by ICAM-1(8-22) and PD 98059. The Fg : ICAM-1 endothelial cell survival pathway appears to be mediated via the activation and upregulation of ERK-1/2 and A1.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Annexin A5 / pharmacology
  • Apoptosis / drug effects
  • Cell Adhesion / drug effects
  • Cell Division / drug effects
  • Cell Separation
  • Cell Survival / drug effects
  • Cells, Cultured
  • Cytochalasin B / pharmacology
  • Cytoskeleton / metabolism
  • Dose-Response Relationship, Drug
  • Endothelium, Vascular / drug effects
  • Endothelium, Vascular / metabolism*
  • Enzyme Inhibitors / pharmacology
  • Fibrinogen / chemistry
  • Fibrinogen / metabolism*
  • Flavonoids / pharmacology
  • Flow Cytometry
  • Humans
  • Intercellular Adhesion Molecule-1 / metabolism*
  • Intercellular Adhesion Molecule-1 / physiology*
  • MAP Kinase Signaling System
  • Mitogen-Activated Protein Kinase 1 / metabolism
  • Mitogen-Activated Protein Kinase 3
  • Mitogen-Activated Protein Kinases / metabolism
  • Nocodazole / pharmacology
  • Phosphorylation / drug effects
  • Reverse Transcriptase Polymerase Chain Reaction
  • Signal Transduction / drug effects
  • Time Factors
  • Transfection
  • Tumor Necrosis Factor-alpha / pharmacology
  • Umbilical Veins / drug effects
  • Umbilical Veins / metabolism*
  • Up-Regulation


  • Annexin A5
  • Enzyme Inhibitors
  • Flavonoids
  • Tumor Necrosis Factor-alpha
  • Intercellular Adhesion Molecule-1
  • Cytochalasin B
  • Fibrinogen
  • Mitogen-Activated Protein Kinase 1
  • Mitogen-Activated Protein Kinase 3
  • Mitogen-Activated Protein Kinases
  • Nocodazole
  • 2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one