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Article
Nature Medicine  9, 407 - 415 (2003)
Published online: 24 March 2003; | doi:10.1038/nm846

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

Jian Hua Qi1, Quteba Ebrahem1, Nina Moore1, Gillian Murphy2, Lena Claesson-Welsh3, Mark Bond4, Andrew Baker5 & Bela Anand-Apte1, 6

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

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

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

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

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

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

Correspondence should be addressed to Bela Anand-Apte anandab@ccf.org
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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Nature Medicine
ISSN: 1078-8956
EISSN: 1546-170X
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