Matrix metalloproteinases cleave connective tissue growth factor and reactivate angiogenic activity of vascular endothelial growth factor 165

Gakuji Hashimoto, Isao Inoki, Yutaka Fujii, Takanori Aoki, Eiji Ikeda, Yasunori Okada

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Abstract

Vascular endothelial growth factor (VEGF), a potent angiogenic mitogen, plays a crucial role in angiogenesis under various pathophysiological conditions. We have recently demonstrated that VEGF 165, one of the VEGF isoforms, binds connective tissue growth factor (CTGF) and that its angiogenic activity is inhibited in the VEGF 165·CTGF complex form (Inoki, I., Shiomi, T., Hashimoto, G., Enomoto, H., Nakamura, H., Makino, K., Ikeda, E., Takata, S., Kobayashi, K. and Okada, Y. (2002) FASEB J. 16, 219-221). In the present study, we further examined the susceptibility of the VEGF 165·CTGF complex to matrix metalloproteinases (MMP-1, -2, -3, -7, -9, and -13), ADAMTS4 (aggrecanase-1), and serine proteinases, and evaluated the recovery of the angiogenic activity of VEGF 165 after the treatment. Among the MMPs, MMP-1, -3, -7, and -13 processed CTGF of the complex into the major NH 2- and COOH-terminal fragments, whereas VEGF 165 was completely resistant to the MMPs. On the other hand, elastase and plasmin cleaved both CTGF and VEGF 165 of the complex, but they were completely resistant to ADAMTS4. By digestion of the immobilized VEGF 165·CTGF complex with MMP-3 or MMP-7, both NH 2- and COOH-terminal fragments of CTGF were dissociated and released from the complex into the liquid phase. The in vitro angiogenic activity of VEGF 165 blocked in the VEGF 165·CTGF complex was reactivated to original levels after CTGF digestion of the complex with MMP-1, -3, and -13. Recovery of angiogenic activity was further confirmed by in vivo angiogenesis assay using a Matrigel injection model in mice. These results demonstrate for the first time that CTGF is a substrate of MMPs and that the angiogenic activity of VEGF 165 suppressed by the complex formation with CTGF is recovered through the selective degradation of CTGF by MMPs. MMPs may play a novel role through CTGF degradation in VEGF-induced angiogenesis during embryonic development, tissue maintenance, and/or pathological processes of various diseases.

Original languageEnglish
Pages (from-to)36288-36295
Number of pages8
JournalJournal of Biological Chemistry
Volume277
Issue number39
DOIs
Publication statusPublished - 2002 Sep 27

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ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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