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

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  • Kevin P. Mouillesseaux

    (The University of North Carolina at Chapel Hill
    Lineberger Comprehensive Cancer Center, 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
    McAllister Heart Institute, The University of North Carolina at Chapel Hill)

  • Suk-Won Jin

    (Section of Cardiovascular Medicine, Yale Cardiovascular Research Center, School of Medicine, Yale University
    School of Life Sciences and Cell Logistics Research Center, Gwangju Institute of Science and Technology)

  • Victoria L. Bautch

    (The University of North Carolina at Chapel Hill
    Lineberger Comprehensive Cancer Center, The University of North Carolina at Chapel Hill
    Curriculum in Genetics and Molecular Biology, The University of North Carolina at Chapel Hill
    McAllister Heart Institute, The University of North Carolina at Chapel Hill)

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.

Suggested Citation

  • 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 Sa, 2016. "Notch regulates BMP responsiveness and lateral branching in vessel networks via SMAD6," Nature Communications, Nature, vol. 7(1), pages 1-12, December.
    • Handle: RePEc:nat:natcom:v:7:y:2016:i:1:d:10.1038_ncomms13247
    DOI: 10.1038/ncomms13247
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    Cited by:

    1. Eun-A Kwak & Christopher C. Pan & Aaron Ramonett & Sanjay Kumar & Paola Cruz-Flores & Tasmia Ahmed & Hannah R. Ortiz & Jeffrey J. Lochhead & Nathan A. Ellis & Ghassan Mouneimne & Teodora G. Georgieva , 2022. "βIV-spectrin as a stalk cell-intrinsic regulator of VEGF signaling," Nature Communications, Nature, vol. 13(1), pages 1-14, December.
    2. Nicholas W. Chavkin & Gael Genet & Mathilde Poulet & Erin D. Jeffery & Corina Marziano & Nafiisha Genet & Hema Vasavada & Elizabeth A. Nelson & Bipul R. Acharya & Anupreet Kour & Jordon Aragon & Steph, 2022. "Endothelial cell cycle state determines propensity for arterial-venous fate," Nature Communications, Nature, vol. 13(1), pages 1-17, December.
    3. Ruifei Yang & Suyun Fang & Jing Wang & Chunyuan Zhang & Ran Zhang & Di Liu & Yiqiang Zhao & Xiaoxiang Hu & Ning Li, 2017. "Genome-wide analysis of structural variants reveals genetic differences in Chinese pigs," PLOS ONE, Public Library of Science, vol. 12(10), pages 1-18, October.

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