title: Matrix metalloproteinase-19 inhibits growth of endothelial cells by generating angiostatin-like fragments from plasminogen.
abstract: BACKGROUND
  Angiogenesis is the process of forming new blood vessels from existing ones and requires degradation of the vascular basement membrane and remodeling of extracellular matrix (ECM) in order to allow endothelial cells to migrate and invade into the surrounding tissue. Matrix metalloproteinases (MMPs) are considered to play a central role in the remodeling of basement membranes and ECM. However, MMPs contribute to vascular remodeling not only by degrading ECM components. Specific MMPs enhance angiogenesis via several ways; they help pericytes to detach from vessels undergoing angiogenesis, release ECM-bound angiogenic growth factors, expose cryptic pro-angiogenic integrin binding sites in the ECM, generate promigratory ECM component fragments, and cleave endothelial cell-cell adhesions. MMPs can also negatively influence the angiogenic process through generating endogenous angiogenesis inhibitors by proteolytic cleavage. Angiostatin, a proteolytic fragment of plasminogen, is one of the most potent antagonists of angiogenesis that inhibits migration and proliferation of endothelial cells. Reports have shown that metalloelastase, pancreas elastase, plasmin reductase, and plasmin convert plasminogen to angiostatin.
  
  
  RESULTS
  We report here that MMP-19 processes human plasminogen in a characteristic cleavage pattern to generate three angiostatin-like fragments with a molecular weight of 35, 38, and 42 kDa. These fragments released by MMP-19 significantly inhibited the proliferation of HMEC cells by 27% (p = 0.01) and reduced formation of capillary-like structures by 45% (p = 0.05) compared with control cells. As it is known that angiostatin blocks hepatocyte growth factor (HGF)-induced pro-angiogenic signaling in endothelial cells due to structural similarities to HGF, we have analyzed if the plasminogen fragments generated by MMP-19 interfere with this pathway. As it involves the activation of c-met, the receptor of HGF, we could show that MMP-19-dependent processing of plasminogen decreases the phosphorylation of c-met.
  
  
  CONCLUSIONS
  Altogether, MMP-19 exhibits an anti-angiogenic effect on endothelial cells via generation of angiostatin-like fragments.
authors.affiliation: Institute of Biochemistry, University of Kiel, Kiel, Germany.
authors.forename: Rena
authors.initials: R
authors.lastname: Brauer
authors.forename: Inken M
authors.initials: IM
authors.lastname: Beck
authors.forename: Martin
authors.initials: M
authors.lastname: Roderfeld
authors.forename: Elke
authors.initials: E
authors.lastname: Roeb
authors.forename: Radislav
authors.initials: R
authors.lastname: Sedlacek
mesh_terms: D020533:Angiogenesis Inhibitors / Q000378:metabolism / Q000494:pharmacology; D043168:Angiostatins / Q000378:metabolism*; D002196:Capillaries / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D042783:Endothelial Cells / Q000187:drug effects* / Q000378:metabolism; D004730:Endothelium, Vascular / Q000166:cytology / Q000187:drug effects; D005982:Glutathione Transferase / Q000235:genetics / Q000378:metabolism; D006801:Humans; D053505:Matrix Metalloproteinases, Secreted / Q000235:genetics / Q000378:metabolism*; D008970:Molecular Weight; D010446:Peptide Fragments / Q000378:metabolism / Q000494:pharmacology*; D010766:Phosphorylation; D010958:Plasminogen / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D019859:Proto-Oncogene Proteins c-met / Q000378:metabolism; D011994:Recombinant Proteins / Q000235:genetics / Q000378:metabolism; D013379:Substrate Specificity
chemical_list: D020533:Angiogenesis Inhibitors; D010446:Peptide Fragments; D011994:Recombinant Proteins; D043168:Angiostatins; D010958:Plasminogen; D005982:Glutathione Transferase; D019859:Proto-Oncogene Proteins c-met; D051057:Proto-Oncogene Proteins c-akt; D053505:Matrix Metalloproteinases, Secreted; C108362:matrix metalloproteinase 19