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A novel function for tissue inhibitor of metalloproteinases-3 (TIMP3): inhibition of angiogenesis by blockage of VEGF binding to VEGF receptor-2

Nature Medicine volume 9, pages 407–415 (2003)Cite this article

Abstract

Tissue inhibitor of metalloproteinases-3 (TIMP3) is one of four members of a family of proteins that were originally classified according to their ability to inhibit matrix metalloproteinases (MMP). TIMP3, which encodes a potent angiogenesis inhibitor, is mutated in Sorsby fundus dystrophy, a macular degenerative disease with submacular choroidal neovascularization. In this study we demonstrate the ability of TIMP3 to inhibit vascular endothelial factor (VEGF)–mediated angiogenesis and identify the potential mechanism by which this occurs: TIMP3 blocks the binding of VEGF to VEGF receptor-2 and inhibits downstream signaling and angiogenesis. This property seems to be independent of its MMP-inhibitory activity, indicating a new function for this molecule.

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Figure 1: TIMP3 inhibits VEGF-mediated angiogenesis.
Figure 2: TIMP3 inhibits VEGF-mediated endothelial cell proliferation.
Figure 3: TIMP3 inhibits KDR-mediated signaling.
Figure 4: TIMP3 inhibits binding of VEGF to its receptor, KDR.
Figure 5: TIMP3 inhibits binding of VEGF to KDR but not to Flt-1.
Figure 6: TIMP3 interacts with KDR.

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Acknowledgements

This work was supported by grant 1 R29 EY12109-01 from the National Institutes of Health, module grant (Foundation Fighting Blindness) and seed grant (Cleveland Clinic Foundation), all to B.A.-A. We thank J. Lang for photography, T. Burke (CCF) for instruction in protein radiolabeling, P. DiCorleto for discussions and P. Salvado for advice on graphics. We sincerely apologize to colleagues whose work was not cited because of space limitations.

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Authors and Affiliations

  1. Department of Ophthalmic Research, Cole Eye Institute, Cleveland Clinic Foundation, Cleveland, Ohio, USA

    Jian Hua Qi, Quteba Ebrahem, Nina Moore & Bela Anand-Apte

  2. Department of Oncology, Cambridge University, Institute for Medical Research, Cambridge, UK

    Gillian Murphy

  3. Departments of Genetics and Pathology, Uppsala University, Vascular Biology Unit, Rudbeck Laboratory, Uppsala, Sweden

    Lena Claesson-Welsh

  4. Bristol Heart Institute, Bristol Royal Infirmary, University of Bristol, Bristol, UK

    Mark Bond

  5. Department of Medicine and Therapeutics, University of Glasgow, Glasgow, UK

    Andrew Baker

  6. Department of Cell Biology, Lerner Research Institute, Cleveland Clinic Foundation, Cleveland, Ohio, USA

    Bela Anand-Apte

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Correspondence to Bela Anand-Apte.

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Qi, J., Ebrahem, Q., Moore, N. et al. A novel function for tissue inhibitor of metalloproteinases-3 (TIMP3): inhibition of angiogenesis by blockage of VEGF binding to VEGF receptor-2. Nat Med 9, 407–415 (2003). https://doi.org/10.1038/nm846

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