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: 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
• Journal: Proceedings of the National Academy of Sciences of the United States of America (Proc Natl Acad Sci U S A) Vol. 110 Issue 47 Pg. 18940-5 (Nov 19 2013) ISSN: 1091-6490 [Electronic] United States
• PMID: 24133138 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• DNA Primers
• Growth Differentiation Factor 2
• ACVRL1 protein, human
• Activin Receptors, Type II

Topics

• Activin Receptors, Type II (metabolism)
• Analysis of Variance
• Animals
• DNA Primers (genetics)
• Diaphragm (pathology)
• Gene Expression Profiling
• Growth Differentiation Factor 2 (metabolism)
• HEK293 Cells
• Histological Techniques
• Humans
• Immunohistochemistry
• In Situ Nick-End Labeling
• Lymphatic Vessels (physiology)
• Mice
• Mice, Inbred BALB C
• Mice, Inbred C57BL
• Microscopy, Fluorescence
• Neovascularization, Pathologic (physiopathology)
• Neovascularization, Physiologic (physiology)
• Peritonitis (physiopathology)
• RNA Interference
• Reverse Transcriptase Polymerase Chain Reaction
• Signal Transduction (physiology)