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.
Highlights
Functional blood vessel growth depends on generation of distinct but coordinated responses from endothelial cells
We first determined the effects of BMP6 and BMP2 on vessel branching in a three-dimensional (3D) sprouting angiogenesis assay[21] using human umbilical vein endothelial cells (HUVEC)
The Bone morphogenetic proteins (BMP)-induced branching phenotype was remarkably well- organized, in contrast to the effects of elevated vascular endothelial growth factor (VEGF)-A signalling, which often lead to gross dysmorphogenesis[22,23]
Summary
Functional blood vessel growth depends on generation of distinct but coordinated responses from endothelial cells. 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. 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. The type I BMP receptor ALK1 is either anti-angiogenic or pro-angiogenic when inhibited by Fc-conjugation or a highly specific blocking antibody, respectively[10,13] These data suggest that the angiogenic activity of BMP ligands is context dependent. Notch sets responsiveness by regulating the cell-intrinsic BMP inhibitor, SMAD6 and SMAD6 affects BMP responses upstream of target gene expression, revealing a new paradigm for Notch-dependent regulation of angiogenesis
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