TIMP-1 promotes VEGF-induced neovascularization in the retina

• Yamada, E. ^[1] ; Tobe, T. ^[1] ; Yamada, H. ^[1] ; Okamoto, N. ^[1] ; Zack, D.J. ^[1] ; Werb, Z. ^[2] ; Soloway, P.D. ^[3] ; Campochiaro, P.A. ^[1]
  1. [1] Johns Hopkins University

     Johns Hopkins University

     Estados Unidos

     
  2. [2] University of California System

     University of California System

     Estados Unidos

     
  3. [3] Roswell Park Cancer Institute

     Roswell Park Cancer Institute

     City of Buffalo, Estados Unidos

     

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• Localización: Histology and histopathology: cellular and molecular biology, ISSN-e 1699-5848, ISSN 0213-3911, Vol. 16, Nº. 1, 2001, págs. 87-97
• Idioma: inglés
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  • Proteolysis of vascular basement membranes and surrounding extracellular matrix is a critical early step in neovascularization. It requires alteration of the balance between matrix metalloproteinases (MMPs) and proteins that bind to and inactivate MMPs, tissue inhibitors of metalloproteinases (TIMPs). TIMP-1 has been demonstrated to inhibit neovascularization in chick chorioallantoic membranes. However, TIMP-1 has also been shown to either promote or inhibit cell proliferation and migration in different settings. To determine whether genetic alteration of the MMPffIMP-1 ratio would alter retinal neovascularization, we crossed mice that express vascu l ar endothelial growth factor (VEGF) in photoreceptors with TIMP-1-deficient mice or mice that overexpress TIMP-l. Compared to VEGF transgeneposi tive/TI MP-1-su fficient mice , VEG F transgenepositive/TIMP-1-deficient mice showed smaller neovascular lesions. There was also no difference between the two groups of mice in the appearance of the neovascularization by light or electron microscopy.

    Compound VEGF/TIMP-1 transgenic mice had increased expression of both VEGF and TIMP-1 in the retina, and had more neovascularization than mice that had increased expression of VEGF alone. These gainand loss-of-function data suggest that alteration of the TIMP-1/MMP ratio modulates retinal neovascularization in a complex manner and not simply by altering the proteolytic activity and thereby invasiveness of endothelial cells.