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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; Lee, Yulia G.; Akatsu, Yuichi; Taguchi, Luna; Suzuki, Hiroshi I.; Cunha, Sara I.; Maruyama, Kazuichi; Suzuki, Yuka; Yamazaki, Tomoko and Katsura, Akihiro, et al. (2013) In Proceedings of the National Academy of Sciences 110(47). p.18940-18945
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)-beta/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... (More)
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)-beta/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. (Less)
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publication status
published
subject
keywords
lymphangiogenesis, angiogenesis, blood vascular endothelial cells
in
Proceedings of the National Academy of Sciences
volume
110
issue
47
pages
18940 - 18945
publisher
National Acad Sciences
external identifiers
  • wos:000327100600059
  • scopus:84888084861
ISSN
1091-6490
DOI
10.1073/pnas.1310479110
language
English
LU publication?
yes
id
4d7f4c99-319c-4aea-84cc-9b3303a3f0bb (old id 4196644)
date added to LUP
2014-01-02 11:52:45
date last changed
2019-03-13 12:23:13
@article{4d7f4c99-319c-4aea-84cc-9b3303a3f0bb,
  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)-beta/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.},
  author       = {Yoshimatsu, Yasuhiro and Lee, Yulia G. and Akatsu, Yuichi and Taguchi, Luna and Suzuki, Hiroshi I. and Cunha, Sara I. and Maruyama, Kazuichi and Suzuki, Yuka and Yamazaki, Tomoko and Katsura, Akihiro and Oh, S. Paul and Zimmers, Teresa A. and Lee, Se-Jin and Pietras, Kristian and Koh, Gou Young and Miyazono, Kohei and Watabe, Tetsuro},
  issn         = {1091-6490},
  keyword      = {lymphangiogenesis,angiogenesis,blood vascular endothelial cells},
  language     = {eng},
  number       = {47},
  pages        = {18940--18945},
  publisher    = {National Acad Sciences},
  series       = {Proceedings of the National Academy of Sciences},
  title        = {Bone morphogenetic protein-9 inhibits lymphatic vessel formation via activin receptor-like kinase 1 during development and cancer progression},
  url          = {http://dx.doi.org/10.1073/pnas.1310479110},
  volume       = {110},
  year         = {2013},
}