TIMP-1 inhibits microvascular endothelial cell migration by MMP-dependent and MMP-independent mechanisms

Exp Cell Res. 2004 Dec 10;301(2):158-67. doi: 10.1016/j.yexcr.2004.08.002.


It was reported over a decade ago that tissue inhibitor of metalloproteinases-1 (TIMP-1) suppresses angiogenesis in experimental models but the mechanism is still incompletely understood. This in vitro study focused on the molecular basis of TIMP-1-mediated inhibition of endothelial cell (EC) migration, a key step in the angiogenic process. Both recombinant human TIMP-1 and the synthetic MMP inhibitors, GM6001 and MMP-2-MMP-9 Inhibitor III, suppressed migration of human dermal microvascular endothelial cells (HDMVEC) in a dose-dependent fashion. The MMP-dependent inhibition of migration was associated with increased expression of the junctional adhesion proteins, VE-cadherin and PECAM-1, and VE-cadherin accumulation at cell-cell junctions. TIMP-1 also caused MMP-independent dephosphorylation of focal adhesion kinase (FAK) (pY397) and paxillin, which was associated with reduced number of F-actin stress fibers and focal adhesions. Moreover, TIMP-1 stimulated expression of PTEN that has been shown to reduce phosphorylation of FAK and inhibit cell migration. Our data suggest that TIMP-1 inhibits HDMVEC migration through MMP-dependent stimulation of VE-cadherin and MMP-independent stimulation of PTEN with subsequent dephosphorylation of FAK and cytoskeletal remodeling.

MeSH terms

  • Antigens, CD
  • Cadherins / metabolism
  • Cells, Cultured
  • Chemotaxis / drug effects*
  • Cytoskeleton / metabolism
  • Dose-Response Relationship, Drug
  • Endothelium, Vascular / cytology*
  • Enzyme Inhibitors / pharmacology
  • Focal Adhesion Kinase 1
  • Focal Adhesion Protein-Tyrosine Kinases
  • Humans
  • Matrix Metalloproteinase Inhibitors
  • Matrix Metalloproteinases / physiology*
  • Microcirculation
  • Neovascularization, Physiologic
  • PTEN Phosphohydrolase
  • Phosphoric Monoester Hydrolases / metabolism
  • Phosphorylation
  • Protein-Tyrosine Kinases / metabolism
  • Tissue Inhibitor of Metalloproteinase-1 / pharmacology*
  • Tumor Suppressor Proteins / metabolism


  • Antigens, CD
  • Cadherins
  • Enzyme Inhibitors
  • Matrix Metalloproteinase Inhibitors
  • Tissue Inhibitor of Metalloproteinase-1
  • Tumor Suppressor Proteins
  • cadherin 5
  • Protein-Tyrosine Kinases
  • Focal Adhesion Kinase 1
  • Focal Adhesion Protein-Tyrosine Kinases
  • PTK2 protein, human
  • Phosphoric Monoester Hydrolases
  • PTEN Phosphohydrolase
  • PTEN protein, human
  • Matrix Metalloproteinases