title: Increased neovascularization in mice lacking tissue inhibitor of metalloproteinases-3.
abstract: OBJECTIVE
  Tissue inhibitor of metalloproteinases-3 (TIMP-3) is a matrix-bound inhibitor of matrix metalloproteinases (MMPs). The authors have previously determined a novel function of TIMP-3 to inhibit vascular endothelial growth factor (VEGF)-mediated angiogenesis. Here, the authors examined the in vivo angiogenic phenotype of ocular vessels in mice deficient in TIMP-3.
  
  
  METHODS
  VEGF-mediated corneal neovascularization and laser-induced choroidal neovascularization (CNV) were examined in TIMP-3-null mice. The effects of the absence of TIMP-3 on the phosphorylation status of the VEGF-receptor-2 (VEGFR-2) and the downstream signaling pathways were evaluated biochemically. In addition, the activation state of MMPs in the retina of TIMP-3-deficient mice was examined by in situ zymography.
  
  
  RESULTS
  The results of these studies determine an accentuation of pathologic VEGF-mediated angiogenesis in the cornea and laser-induced CNV in mice lacking TIMP-3. In the absence of the MMP inhibitor, pathophysiological changes were observed in the choroidal vasculature concomitantly with an increase in gelatinolytic activity. These results suggest that an imbalance of extracellular matrix homeostasis, together with a loss of an angiogenesis inhibitor, can prime vascular beds to be more responsive to an angiogenic stimulus.
  
  
  CONCLUSIONS
  In light of the recent studies suggesting that genetic variants near TIMP-3 influence susceptibility to age-related macular degeneration, these results imply that TIMP-3 may regulate the development of the choroidal vasculature and is a likely contributor to increased susceptibility to choroidal neovascularization.
authors.affiliation: Department of Ophthalmology, Cole Eye Institute, Cleveland Clinic Lerner College of Medicine, Cleveland, Ohio 44195, USA.
authors.forename: Quteba
authors.initials: Q
authors.lastname: Ebrahem
authors.forename: Jian Hua
authors.initials: JH
authors.lastname: Qi
authors.forename: Masahiko
authors.initials: M
authors.lastname: Sugimoto
authors.forename: Mariya
authors.initials: M
authors.lastname: Ali
authors.forename: Jonathan E
authors.initials: JE
authors.lastname: Sears
authors.forename: Alecia
authors.initials: A
authors.lastname: Cutler
authors.forename: Rama
authors.initials: R
authors.lastname: Khokha
authors.forename: Amit
authors.initials: A
authors.lastname: Vasanji
authors.forename: Bela
authors.initials: B
authors.lastname: Anand-Apte
mesh_terms: D000818:Animals; D020256:Choroidal Neovascularization / Q000378:metabolism / Q000503:physiopathology*; D016510:Corneal Neovascularization / Q000378:metabolism / Q000503:physiopathology*; D004195:Disease Models, Animal; D015151:Immunoblotting; D047468:Immunoprecipitation; D017075:Laser Coagulation; D019278:Matrix Metalloproteinase 3 / Q000502:physiology; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009887:Ophthalmoscopy; D010766:Phosphorylation; D019717:Tissue Inhibitor of Metalloproteinase-3 / Q000172:deficiency*; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000378:metabolism
chemical_list: D019717:Tissue Inhibitor of Metalloproteinase-3; C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A; D040301:Vascular Endothelial Growth Factor Receptor-2; D019278:Matrix Metalloproteinase 3; C511769:Mmp3 protein, mouse