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

HLX Wong, G Jin, R Cao, S Zhang, Y Cao… - Nature …, 2016 - nature.com
HLX Wong, G Jin, R Cao, S Zhang, Y Cao, Z Zhou
Nature communications, 2016nature.com
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 …
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.
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