title: 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)-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 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.
authors.affiliation: Department of Molecular Pathology, Graduate School of Medicine, The University of Tokyo, Bunkyo-ku, Tokyo 113-0033, Japan.
authors.forename: Yasuhiro
authors.initials: Y
authors.lastname: Yoshimatsu
authors.forename: Yulia G
authors.initials: YG
authors.lastname: Lee
authors.forename: Yuichi
authors.initials: Y
authors.lastname: Akatsu
authors.forename: Luna
authors.initials: L
authors.lastname: Taguchi
authors.forename: Hiroshi I
authors.initials: HI
authors.lastname: Suzuki
authors.forename: Sara I
authors.initials: SI
authors.lastname: Cunha
authors.forename: Kazuichi
authors.initials: K
authors.lastname: Maruyama
authors.forename: Yuka
authors.initials: Y
authors.lastname: Suzuki
authors.forename: Tomoko
authors.initials: T
authors.lastname: Yamazaki
authors.forename: Akihiro
authors.initials: A
authors.lastname: Katsura
authors.forename: S Paul
authors.initials: SP
authors.lastname: Oh
authors.forename: Teresa A
authors.initials: TA
authors.lastname: Zimmers
authors.forename: Se-Jin
authors.initials: SJ
authors.lastname: Lee
authors.forename: Kristian
authors.initials: K
authors.lastname: Pietras
authors.forename: Gou Young
authors.initials: GY
authors.lastname: Koh
authors.forename: Kohei
authors.initials: K
authors.lastname: Miyazono
authors.forename: Tetsuro
authors.initials: T
authors.lastname: Watabe
mesh_terms: D030301:Activin Receptors, Type II / Q000378:metabolism*; D000704:Analysis of Variance; D000818:Animals; D017931:DNA Primers / Q000235:genetics; D003964:Diaphragm / Q000473:pathology; D020869:Gene Expression Profiling; D055427:Growth Differentiation Factor 2 / Q000378:metabolism*; D057809:HEK293 Cells; D006652:Histological Techniques; D006801:Humans; D007150:Immunohistochemistry; D020287:In Situ Nick-End Labeling; D042601:Lymphatic Vessels / Q000502:physiology*; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D008856:Microscopy, Fluorescence; D009389:Neovascularization, Pathologic / Q000503:physiopathology*; D018919:Neovascularization, Physiologic / Q000502:physiology*; D010538:Peritonitis / Q000503:physiopathology*; D034622:RNA Interference; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000502:physiology*
chemical_list: D017931:DNA Primers; D055427:Growth Differentiation Factor 2; C425364:ACVRL1 protein, human; D030301:Activin Receptors, Type II
keywords: angiogenesis; blood vascular endothelial cells; lymphangiogenesis