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

Yasuhiro Yoshimatsu, Yulia G. Lee, Yuichi Akatsu, Luna Taguchi, Hiroshi I. Suzuki, Sara I. Cunha, Kazuichi Maruyama, Yuka Suzuki, Tomoko Yamazaki, Akihiro Katsura, S. Paul Oh, Teresa Zimmers, Se Jin Lee, Kristian Pietras, Gou Young Koh, Kohei Miyazono, Tetsuro Watabe

Research output: Contribution to journalArticle

55 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)18940-18945
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume110
Issue number47
DOIs
StatePublished - Nov 19 2013
Externally publishedYes

Fingerprint

Growth Differentiation Factor 2
Activin Receptors
Lymphatic Vessels
Neoplasms
Endothelial Cells
Homeobox Genes
Bone Morphogenetic Protein Receptors
Hereditary Hemorrhagic Telangiectasia
Transforming Growth Factors
Vascular Diseases
Carcinogenesis
Homeostasis
Transcription Factors
Down-Regulation
Embryonic Structures
Maintenance
Cell Proliferation
Neoplasm Metastasis
Inflammation
Skin

ASJC Scopus subject areas

  • General

Cite this

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; Katsura, Akihiro; Oh, S. Paul; Zimmers, Teresa; Lee, Se Jin; Pietras, Kristian; Koh, Gou Young; Miyazono, Kohei; Watabe, Tetsuro.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 110, No. 47, 19.11.2013, p. 18940-18945.

Research output: Contribution to journalArticle

Yoshimatsu, Y, Lee, YG, Akatsu, Y, Taguchi, L, Suzuki, HI, Cunha, SI, Maruyama, K, Suzuki, Y, Yamazaki, T, Katsura, A, Oh, SP, Zimmers, T, Lee, SJ, Pietras, K, Koh, GY, Miyazono, K & Watabe, T 2013, 'Bone morphogenetic protein-9 inhibits lymphatic vessel formation via activin receptor-like kinase 1 during development and cancer progression', Proceedings of the National Academy of Sciences of the United States of America, vol. 110, no. 47, pp. 18940-18945. https://doi.org/10.1073/pnas.1310479110
Yoshimatsu, Yasuhiro ; Lee, Yulia G. ; Akatsu, Yuichi ; Taguchi, Luna ; Suzuki, Hiroshi I. ; Cunha, Sara I. ; Maruyama, Kazuichi ; Suzuki, Yuka ; Yamazaki, Tomoko ; Katsura, Akihiro ; Oh, S. Paul ; Zimmers, Teresa ; Lee, Se Jin ; Pietras, Kristian ; Koh, Gou Young ; Miyazono, Kohei ; Watabe, Tetsuro. / Bone morphogenetic protein-9 inhibits lymphatic vessel formation via activin receptor-like kinase 1 during development and cancer progression. In: Proceedings of the National Academy of Sciences of the United States of America. 2013 ; Vol. 110, No. 47. pp. 18940-18945.
@article{416065ef32c74de2818c7dab5a2c0619,
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)-?/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 = "Yasuhiro Yoshimatsu and Lee, {Yulia G.} and Yuichi Akatsu and Luna Taguchi and Suzuki, {Hiroshi I.} and Cunha, {Sara I.} and Kazuichi Maruyama and Yuka Suzuki and Tomoko Yamazaki and Akihiro Katsura and Oh, {S. Paul} and Teresa Zimmers and Lee, {Se Jin} and Kristian Pietras and Koh, {Gou Young} and Kohei Miyazono and Tetsuro Watabe",
year = "2013",
month = "11",
day = "19",
doi = "10.1073/pnas.1310479110",
language = "English (US)",
volume = "110",
pages = "18940--18945",
journal = "Proceedings of the National Academy of Sciences of the United States of America",
issn = "0027-8424",
number = "47",

}

TY - JOUR

T1 - Bone morphogenetic protein-9 inhibits lymphatic vessel formation via activin receptor-like kinase 1 during development and cancer progression

AU - Yoshimatsu, Yasuhiro

AU - Lee, Yulia G.

AU - Akatsu, Yuichi

AU - Taguchi, Luna

AU - Suzuki, Hiroshi I.

AU - Cunha, Sara I.

AU - Maruyama, Kazuichi

AU - Suzuki, Yuka

AU - Yamazaki, Tomoko

AU - Katsura, Akihiro

AU - Oh, S. Paul

AU - Zimmers, Teresa

AU - Lee, Se Jin

AU - Pietras, Kristian

AU - Koh, Gou Young

AU - Miyazono, Kohei

AU - Watabe, Tetsuro

PY - 2013/11/19

Y1 - 2013/11/19

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=84888084861&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84888084861&partnerID=8YFLogxK

U2 - 10.1073/pnas.1310479110

DO - 10.1073/pnas.1310479110

M3 - Article

VL - 110

SP - 18940

EP - 18945

JO - Proceedings of the National Academy of Sciences of the United States of America

JF - Proceedings of the National Academy of Sciences of the United States of America

SN - 0027-8424

IS - 47

ER -