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

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.

journal_name

Nat Commun

journal_title

Nature communications

authors

Mouillesseaux KP,Wiley DS,Saunders LM,Wylie LA,Kushner EJ,Chong DC,Citrin KM,Barber AT,Park Y,Kim JD,Samsa LA,Kim J,Liu J,Jin SW,Bautch VL

doi

10.1038/ncomms13247

subject

Has Abstract

pub_date

2016-11-11 00:00:00

pages

13247

issn

2041-1723

pii

ncomms13247

journal_volume

7

pub_type

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