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Nat Commun. 2016 Nov 11;7:13247. doi: 10.1038/ncomms13247.

Notch regulates BMP responsiveness and lateral branching in vessel networks via SMAD6.

Author information

1
Department of Biology, The University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599, USA.
2
Lineberger Comprehensive Cancer Center, The University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599, USA.
3
Curriculum in Genetics and Molecular Biology, The University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599, USA.
4
Department of Life Systems, Sookmyung Women's University, Seoul, Korea.
5
Section of Cardiovascular Medicine, Department of Internal Medicine, Yale Cardiovascular Research Center, School of Medicine, Yale University, New Haven, Connecricut 06511, USA.
6
Department of Pathology and Laboratory Animal Medicine, The University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599, USA.
7
McAllister Heart Institute, The University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599, USA.
8
School of Life Sciences and Cell Logistics Research Center, Gwangju Institute of Science and Technology, Gwangju, Korea.

Abstract

Functional blood vessel growth depends on generation of distinct but coordinated responses from endothelial cells. Bone morphogenetic proteins (BMP), part of the TGFβ superfamily, bind receptors to induce phosphorylation and nuclear translocation of SMAD transcription factors (R-SMAD1/5/8) and regulate vessel growth. However, SMAD1/5/8 signalling results in both pro- and anti-angiogenic outputs, highlighting a poor understanding of the complexities of BMP signalling in the vasculature. Here we show that BMP6 and BMP2 ligands are pro-angiogenic in vitro and in vivo, and that lateral vessel branching requires threshold levels of R-SMAD phosphorylation. Endothelial cell responsiveness to these pro-angiogenic BMP ligands is regulated by Notch status and Notch sets responsiveness by regulating a cell-intrinsic BMP inhibitor, SMAD6, which affects BMP responses upstream of target gene expression. Thus, we reveal a paradigm for Notch-dependent regulation of angiogenesis: Notch regulates SMAD6 expression to affect BMP responsiveness of endothelial cells and new vessel branch formation.

PMID:
27834400
PMCID:
PMC5114582
DOI:
10.1038/ncomms13247
[Indexed for MEDLINE]
Free PMC Article

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