title: MT1-MMP sheds LYVE-1 on lymphatic endothelial cells and suppresses VEGF-C production to inhibit lymphangiogenesis.
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.
authors.affiliation: Shenzhen Institute of Research and Innovation, University of Hong Kong, Shenzhen 518057, China.|Li Ka Shing Faculty of Medicine, School of Biomedical Sciences, University of Hong Kong, 21 Sassoon Road, Hong Kong, China.
authors.forename: Hoi Leong Xavier
authors.initials: HL
authors.lastname: Wong
authors.affiliation: Li Ka Shing Faculty of Medicine, School of Biomedical Sciences, University of Hong Kong, 21 Sassoon Road, Hong Kong, China.
authors.forename: Guoxiang
authors.initials: G
authors.lastname: Jin
authors.affiliation: Department of Microbiology and Tumor Center, Karolinska Institute, Stockholm 171 77, Sweden.
authors.forename: Renhai
authors.initials: R
authors.lastname: Cao
authors.affiliation: Shenzhen Institute of Research and Innovation, University of Hong Kong, Shenzhen 518057, China.|Li Ka Shing Faculty of Medicine, School of Biomedical Sciences, University of Hong Kong, 21 Sassoon Road, Hong Kong, China.
authors.forename: Shuo
authors.initials: S
authors.lastname: Zhang
authors.affiliation: Department of Microbiology and Tumor Center, Karolinska Institute, Stockholm 171 77, Sweden.
authors.forename: Yihai
authors.initials: Y
authors.lastname: Cao
authors.affiliation: Shenzhen Institute of Research and Innovation, University of Hong Kong, Shenzhen 518057, China.|Li Ka Shing Faculty of Medicine, School of Biomedical Sciences, University of Hong Kong, 21 Sassoon Road, Hong Kong, China.
authors.forename: Zhongjun
authors.initials: Z
authors.lastname: Zhou
mesh_terms: D000818:Animals; D016025:Bone Transplantation; D002478:Cells, Cultured; D003315:Cornea; D042783:Endothelial Cells / Q000502:physiology*; D005786:Gene Expression Regulation / Q000502:physiology; D006023:Glycoproteins / Q000235:genetics / Q000378:metabolism*; D042583:Lymphangiogenesis / Q000502:physiology*; D008264:Macrophages / Q000502:physiology; D053511:Matrix Metalloproteinase 14 / Q000235:genetics / Q000378:metabolism*; D026901:Membrane Transport Proteins; D051379:Mice; D018345:Mice, Knockout; D042582:Vascular Endothelial Growth Factor C / Q000235:genetics / Q000378:metabolism*
chemical_list: D006023:Glycoproteins; D053511:Matrix Metalloproteinase 14; D026901:Membrane Transport Proteins; D042582:Vascular Endothelial Growth Factor C; C507096:Mmp14 protein, mouse; C492273:LYVE1 protein, mouse; C467483:vascular endothelial growth factor C, mouse