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

Research output: Contribution to journalArticle

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.

Details

Authors
  • 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 A. Zimmers
  • Se-Jin Lee
  • Kristian Pietras
  • Gou Young Koh
  • Kohei Miyazono
  • Tetsuro Watabe
Organisations
Research areas and keywords

Subject classification (UKÄ) – MANDATORY

  • Cancer and Oncology

Keywords

  • lymphangiogenesis, angiogenesis, blood vascular endothelial cells
Original languageEnglish
Pages (from-to)18940-18945
JournalProceedings of the National Academy of Sciences
Volume110
Issue number47
Publication statusPublished - 2013
Publication categoryResearch
Peer-reviewedYes

Bibliographic note

The information about affiliations in this record was updated in December 2015. The record was previously connected to the following departments: Molecular Medicine (013031200)