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, Victoria L. Bautch

Research output: Contribution to journalArticle

40 Scopus citations

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.

Original languageEnglish (US)
Article number13247
JournalNature Communications
Volume7
DOIs
StatePublished - Nov 11 2016

ASJC Scopus subject areas

  • Chemistry(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Physics and Astronomy(all)

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