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Bone morphogenetic protein-9 inhibits lymphatic vessel formation via activin receptor-like kinase 1 during development and cancer progression.


ABSTRACT: Lymphatic vessels (LVs) play critical roles in the maintenance of fluid homeostasis and in pathological conditions, including cancer metastasis. Although mutations in ALK1, a member of the transforming growth factor (TGF)-?/bone morphogenetic protein (BMP) receptor family, have been linked to hereditary hemorrhagic telangiectasia, a human vascular disease, the roles of activin receptor-like kinase 1 (ALK-1) signals in LV formation largely remain to be elucidated. We show that ALK-1 signals inhibit LV formation, and LVs were enlarged in multiple organs in Alk1-depleted mice. These inhibitory effects of ALK-1 signaling were mediated by BMP-9, which decreased the number of cultured lymphatic endothelial cells. Bmp9-deficient mouse embryos consistently exhibited enlarged dermal LVs. BMP-9 also inhibited LV formation during inflammation and tumorigenesis. BMP-9 downregulated the expression of the transcription factor prospero-related homeobox 1, which is necessary to maintain lymphatic endothelial cell identity. Furthermore, silencing prospero-related homeobox 1 expression inhibited lymphatic endothelial cell proliferation. Our findings reveal a unique molecular basis for the physiological and pathological roles of BMP-9/ALK-1 signals in LV formation.

SUBMITTER: Yoshimatsu Y 

PROVIDER: S-EPMC3839734 | biostudies-literature | 2013 Nov

REPOSITORIES: biostudies-literature

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Bone morphogenetic protein-9 inhibits lymphatic vessel formation via activin receptor-like kinase 1 during development and cancer progression.

Yoshimatsu Yasuhiro Y   Lee Yulia G YG   Akatsu Yuichi Y   Taguchi Luna L   Suzuki Hiroshi I HI   Cunha Sara I SI   Maruyama Kazuichi K   Suzuki Yuka Y   Yamazaki Tomoko T   Katsura Akihiro A   Oh S Paul SP   Zimmers Teresa A TA   Lee Se-Jin SJ   Pietras Kristian K   Koh Gou Young GY   Miyazono Kohei K   Watabe Tetsuro T  

Proceedings of the National Academy of Sciences of the United States of America 20131016 47


Lymphatic vessels (LVs) play critical roles in the maintenance of fluid homeostasis and in pathological conditions, including cancer metastasis. Although mutations in ALK1, a member of the transforming growth factor (TGF)-β/bone morphogenetic protein (BMP) receptor family, have been linked to hereditary hemorrhagic telangiectasia, a human vascular disease, the roles of activin receptor-like kinase 1 (ALK-1) signals in LV formation largely remain to be elucidated. We show that ALK-1 signals inhib  ...[more]

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