Cross-talk between vascular endothelial growth factor and matrix metalloproteinases in the induction of neovascularization in vivo

Am J Pathol. 2010 Jan;176(1):496-503. doi: 10.2353/ajpath.2010.080642. Epub 2009 Nov 30.


Matrix metalloproteinases (MMPs), a specialized group of enzymes capable of proteolytically degrading extracellular matrix proteins, have been postulated to play an important role in angiogenesis. It has been suggested that MMPs can regulate neovascularization using mechanisms other than simple remodeling of the capillary basement membrane. To determine the interplay between vascular endothelial growth factor (VEGF) and MMPs, we investigated the induction of angiogenesis by recombinant active MMPs and VEGF in vivo. Using a rat corneal micropocket in vivo angiogenesis assay, we observed that the active form of MMP-9 could induce neovascularization in vivo when compared with the pro- form of the enzyme as a control. This angiogenic response could be inhibited by neutralizing VEGF antibody, which suggests that MMPs acts upstream of VEGF. Additional in vitro studies using extracellular matrix loaded with radiolabeled VEGF determined that active MMPs can enzymatically release sequestered VEGF. Interestingly, in vivo angiogenesis induced by VEGF could be inhibited by MMP inhibitors, indicating that MMPs also act downstream of VEGF. In addition, inflammation plays an important role in the induction of angiogenesis mediated by both VEGF and MMPs. Our results suggest that MMPs act both upstream and downstream of VEGF and imply that potential combination therapies of VEGF and MMP inhibitors may be a useful therapeutic approach in diseases of pathological neovascularization.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Movement / drug effects
  • Cornea / blood supply*
  • Cornea / drug effects
  • Cornea / enzymology*
  • Endothelial Cells / cytology
  • Endothelial Cells / drug effects
  • Endothelial Cells / enzymology
  • Enzyme Activation / drug effects
  • Enzyme Inhibitors / pharmacology
  • Extracellular Matrix / drug effects
  • Extracellular Matrix / metabolism
  • Humans
  • Immunocompromised Host
  • Implants, Experimental
  • Matrix Metalloproteinase 2 / metabolism*
  • Matrix Metalloproteinase 2 / pharmacology
  • Matrix Metalloproteinase 9 / metabolism*
  • Matrix Metalloproteinase 9 / pharmacology
  • Matrix Metalloproteinase Inhibitors
  • Mice
  • Mice, Inbred C57BL
  • Neovascularization, Physiologic* / drug effects
  • Neutralization Tests
  • Rats
  • Vascular Endothelial Growth Factor A / metabolism*
  • Vascular Endothelial Growth Factor A / pharmacology


  • Enzyme Inhibitors
  • Matrix Metalloproteinase Inhibitors
  • Vascular Endothelial Growth Factor A
  • Matrix Metalloproteinase 2
  • Matrix Metalloproteinase 9