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MT1-MMP sheds LYVE-1 on lymphatic endothelial cells and suppresses VEGF-C production to inhibit lymphangiogenesis

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  • Hoi Leong Xavier Wong

    (Shenzhen Institute of Research and Innovation, University of Hong Kong
    Li Ka Shing Faculty of Medicine, School of Biomedical Sciences, University of Hong Kong, 21 Sassoon Road, Hong Kong, China)

  • Guoxiang Jin

    (Li Ka Shing Faculty of Medicine, School of Biomedical Sciences, University of Hong Kong, 21 Sassoon Road, Hong Kong, China)

  • Renhai Cao

    (Karolinska Institute)

  • Shuo Zhang

    (Shenzhen Institute of Research and Innovation, University of Hong Kong
    Li Ka Shing Faculty of Medicine, School of Biomedical Sciences, University of Hong Kong, 21 Sassoon Road, Hong Kong, China)

  • Yihai Cao

    (Karolinska Institute)

  • Zhongjun Zhou

    (Shenzhen Institute of Research and Innovation, University of Hong Kong
    Li Ka Shing Faculty of Medicine, School of Biomedical Sciences, University of Hong Kong, 21 Sassoon Road, Hong Kong, China)

Abstract

Lymphangiogensis is involved in various pathological conditions, such as arthritis and cancer metastasis. Although many factors have been identified to stimulate lymphatic vessel growth, little is known about lymphangiogenesis inhibitors. Here we report that membrane type 1-matrix metalloproteinase (MT1-MMP) is an endogenous suppressor of lymphatic vessel growth. MT1-MMP-deficient mice exhibit spontaneous corneal lymphangiogenesis without concomitant changes in angiogenesis. Mice lacking MT1-MMP in either lymphatic endothelial cells or macrophages recapitulate corneal lymphangiogenic phenotypes observed in Mmp14−/− mice, suggesting that the spontaneous lymphangiogenesis is both lymphatic endothelial cells autonomous and macrophage associated. Mechanistically, MT1-MMP directly cleaves LYVE-1 on lymphatic endothelial cells to inhibit LYVE-1-mediated lymphangiogenic responses. In addition, MT1-MMP-mediated PI3Kδ signalling restrains the production of VEGF-C from prolymphangiogenic macrophages through repressing the activation of NF-κB signalling. Thus, we identify MT1-MMP as an endogenous inhibitor of physiological lymphangiogenesis.

Suggested Citation

  • Hoi Leong Xavier Wong & Guoxiang Jin & Renhai Cao & Shuo Zhang & Yihai Cao & Zhongjun Zhou, 2016. "MT1-MMP sheds LYVE-1 on lymphatic endothelial cells and suppresses VEGF-C production to inhibit lymphangiogenesis," Nature Communications, Nature, vol. 7(1), pages 1-17, April.
    • Handle: RePEc:nat:natcom:v:7:y:2016:i:1:d:10.1038_ncomms10824
    DOI: 10.1038/ncomms10824
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