Journal
NATURE COMMUNICATIONS
Volume 7, Issue -, Pages -Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/ncomms10824
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Funding
- RGC/MOE joint scheme [M-HKU703/13]
- National Science Foundation of China [31271492, 81330009]
- Shenzhen Bureau of Science and Innovation [JCYJ20130401141412387]
- UGC [TbRS T13-607/12]
- RGC [HKU 786013M]
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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 PI3K delta signalling restrains the production of VEGF-C from prolymphangiogenic macrophages through repressing the activation of NF-kappa B signalling. Thus, we identify MT1-MMP as an endogenous inhibitor of physiological lymphangiogenesis.
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