Notch regulates BMP responsiveness and lateral branching in vessel networks via SMAD6.
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.
Department of Biology, The University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599, USA.|Lineberger Comprehensive Cancer Center, The University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599, USA.
Kevin P
KP
Mouillesseaux
Department of Biology, The University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599, USA.
David S
DS
Wiley
Department of Biology, The University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599, USA.
Lauren M
LM
Saunders
Curriculum in Genetics and Molecular Biology, The University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599, USA.
Lyndsay A
LA
Wylie
Department of Biology, The University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599, USA.
Erich J
EJ
Kushner
Curriculum in Genetics and Molecular Biology, The University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599, USA.
Diana C
DC
Chong
Department of Biology, The University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599, USA.
Kathryn M
KM
Citrin
Department of Biology, The University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599, USA.
Andrew T
AT
Barber
Department of Life Systems, Sookmyung Women's University, Seoul, Korea.
Youngsook
Y
Park
Section of Cardiovascular Medicine, Department of Internal Medicine, Yale Cardiovascular Research Center, School of Medicine, Yale University, New Haven, Connecricut 06511, USA.
Jun-Dae
JD
Kim
Department of Pathology and Laboratory Animal Medicine, The University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599, USA.
Leigh Ann
LA
Samsa
Department of Life Systems, Sookmyung Women's University, Seoul, Korea.
Jongmin
J
Kim
Department of Pathology and Laboratory Animal Medicine, The University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599, USA.|McAllister Heart Institute, The University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599, USA.
Jiandong
J
Liu
Section of Cardiovascular Medicine, Department of Internal Medicine, Yale Cardiovascular Research Center, School of Medicine, Yale University, New Haven, Connecricut 06511, USA.|School of Life Sciences and Cell Logistics Research Center, Gwangju Institute of Science and Technology, Gwangju, Korea.
Suk-Won
SW
Jin
Department of Biology, The University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599, USA.|Lineberger Comprehensive Cancer Center, The University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599, USA.|Curriculum in Genetics and Molecular Biology, The University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599, USA.|McAllister Heart Institute, The University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599, USA.
Victoria L
VL
Bautch
D000818:Animals; D019485:Bone Morphogenetic Proteins / Q000235:genetics / Q000378:metabolism*; D002460:Cell Line; D061307:Human Umbilical Vein Endothelial Cells; D006801:Humans; D051379:Mice; D018919:Neovascularization, Physiologic / Q000502:physiology*; D051880:Receptors, Notch / Q000235:genetics / Q000378:metabolism*; D051905:Smad6 Protein / Q000235:genetics / Q000378:metabolism*; D015027:Zebrafish
D019485:Bone Morphogenetic Proteins; D051880:Receptors, Notch; C497802:SMAD6 protein, human; D051905:Smad6 Protein; C497803:Smad6 protein, mouse