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.
Highlights
Lymphangiogensis is involved in various pathological conditions, such as arthritis and cancer metastasis
As Lymphatic vessel endothelial hyaluronan receptor-1 (LYVE-1) is a specific marker for lymphatic endothelial cell (LEC) and a homologue of CD44, a well-documented substrate of membrane type 1-matrix metalloproteinase (MT1-MMP), we examined whether the changes in lymphangiogenic responses of LECs resulting from the loss of MT1-MMP might be related to altered LYVE-1 functions
As LYVE-1 is a predominant receptor for HA on the cell surface of LECs and LYVE-1 is upregulated in Mmp14À/À LECs, we examined whether the accumulation of LYVE-1 resulting from the loss of MT1-MMP may lead to the altered lymphangiogenic responses of LECs to HA stimulation
Summary
Lymphangiogensis is involved in various pathological conditions, such as arthritis and cancer metastasis. Many factors have been identified to stimulate lymphatic vessel growth, little is known about lymphangiogenesis inhibitors. 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. We identify MT1-MMP as an endogenous inhibitor of physiological lymphangiogenesis. Despite its importance in physiology and pathological conditions, the inhibitory factors for lymphatic vessel growth remain largely unknown. Lymphangiogenesis during postnatal development is mainly modulated by the vascular endothelial growth factor-C (VEGF-C). As MT1-MMP-deficient mice exhibit defective fibroblast growth factor-2 (FGF2)-induced corneal angiogenesis[17,22] and impaired blood vessel invasion in endochondrial ossification[17], MT1-MMP is identified as a crucial regulator of blood vessel growth. The role of MT1-MMP in angiogenesis is well established, its function in lymphangiogenesis remains unexplored
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