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

Kevin P. Mouillesseaux, David S. Wiley, Lauren M. Saunders, Lyndsay A. Wylie, Erich J. Kushner, Diana C. Chong, Kathryn M. Citrin, Andrew T. Barber, Youngsook Park, Jun-Dae Kim, Leigh Ann Samsa, Jongmin Kim, Jiandong Liu, Suk-Won Jin () and Victoria L. Bautch ()
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Kevin P. Mouillesseaux: The University of North Carolina at Chapel Hill
David S. Wiley: The University of North Carolina at Chapel Hill
Lauren M. Saunders: The University of North Carolina at Chapel Hill
Lyndsay A. Wylie: Curriculum in Genetics and Molecular Biology, The University of North Carolina at Chapel Hill
Erich J. Kushner: The University of North Carolina at Chapel Hill
Diana C. Chong: Curriculum in Genetics and Molecular Biology, The University of North Carolina at Chapel Hill
Kathryn M. Citrin: The University of North Carolina at Chapel Hill
Andrew T. Barber: The University of North Carolina at Chapel Hill
Youngsook Park: Sookmyung Women’s University
Jun-Dae Kim: Section of Cardiovascular Medicine, Yale Cardiovascular Research Center, School of Medicine, Yale University
Leigh Ann Samsa: The University of North Carolina at Chapel Hill
Jongmin Kim: Sookmyung Women’s University
Jiandong Liu: The University of North Carolina at Chapel Hill
Suk-Won Jin: Section of Cardiovascular Medicine, Yale Cardiovascular Research Center, School of Medicine, Yale University
Victoria L. Bautch: The University of North Carolina at Chapel Hill

Nature Communications, 2016, vol. 7, issue 1, 1-12

Abstract: 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.

Date: 2016
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DOI: 10.1038/ncomms13247

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