Abstract
Tissue inhibitors of metalloproteinases (TIMPs) suppress matrix metalloproteinase (MMP) activity critical for extracellular matrix turnover associated with both physiologic and pathologic tissue remodeling. We demonstrate here that TIMP-2 abrogates angiogenic factor-induced endothelial cell proliferation in vitro and angiogenesis in vivo independent of MMP inhibition. These effects require alpha 3 beta 1 integrin-mediated binding of TIMP-2 to endothelial cells. Further, TIMP-2 induces a decrease in total protein tyrosine phosphatase (PTP) activity associated with beta1 integrin subunits as well as dissociation of the phosphatase SHP-1 from beta1. TIMP-2 treatment also results in a concomitant increase in PTP activity associated with tyrosine kinase receptors FGFR-1 and KDR. Our findings establish an unexpected, MMP-independent mechanism for TIMP-2 inhibition of endothelial cell proliferation in vitro and reveal an important component of the antiangiogenic effect of TIMP2 in vivo.
MeSH terms
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Angiogenesis Inhibitors / genetics
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Angiogenesis Inhibitors / pharmacology*
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Animals
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Binding, Competitive
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Cell Division / drug effects
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Cells, Cultured
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Dose-Response Relationship, Drug
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Embryo, Mammalian / cytology
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Endothelial Growth Factors / metabolism
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Endothelium, Vascular / cytology
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Endothelium, Vascular / drug effects*
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Endothelium, Vascular / metabolism
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Enzyme Inhibitors / pharmacology
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Fibroblast Growth Factor 2 / metabolism
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Fibroblasts / metabolism
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Humans
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Integrin alpha3beta1 / metabolism
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Intracellular Signaling Peptides and Proteins
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Matrix Metalloproteinases / metabolism*
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Mice
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Neovascularization, Physiologic / drug effects
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Neovascularization, Physiologic / physiology*
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Protein Tyrosine Phosphatase, Non-Receptor Type 1
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Protein Tyrosine Phosphatase, Non-Receptor Type 6
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Protein Tyrosine Phosphatases / drug effects
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Protein Tyrosine Phosphatases / metabolism
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Receptor Protein-Tyrosine Kinases / pharmacology
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Receptor, Fibroblast Growth Factor, Type 1
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Receptors, Fibroblast Growth Factor
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Recombinant Proteins / pharmacology
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Tissue Inhibitor of Metalloproteinase-2 / genetics
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Tissue Inhibitor of Metalloproteinase-2 / pharmacology*
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Vanadates / pharmacology
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Vascular Endothelial Growth Factor A
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Vascular Endothelial Growth Factor Receptor-2 / metabolism
Substances
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Angiogenesis Inhibitors
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Endothelial Growth Factors
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Enzyme Inhibitors
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Integrin alpha3beta1
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Intracellular Signaling Peptides and Proteins
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Receptors, Fibroblast Growth Factor
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Recombinant Proteins
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Vascular Endothelial Growth Factor A
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Fibroblast Growth Factor 2
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Tissue Inhibitor of Metalloproteinase-2
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Vanadates
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FGFR1 protein, human
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Fgfr1 protein, mouse
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Receptor Protein-Tyrosine Kinases
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Receptor, Fibroblast Growth Factor, Type 1
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Vascular Endothelial Growth Factor Receptor-2
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PTPN6 protein, human
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Protein Tyrosine Phosphatase, Non-Receptor Type 1
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Protein Tyrosine Phosphatase, Non-Receptor Type 6
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Protein Tyrosine Phosphatases
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Ptpn6 protein, mouse
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Matrix Metalloproteinases