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

doi:10.1038/ncomms13247

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

Houston Methodist

Research output: Contribution to journal › Article › peer-review

71 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 language	English (US)
Article number	13247
Journal	Nature Communications
Volume	7
DOIs	https://doi.org/10.1038/ncomms13247
State	Published - Nov 11 2016

ASJC Scopus subject areas

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

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Mouillesseaux, K. P., Wiley, D. S., Saunders, L. M., Wylie, L. A., Kushner, E. J., Chong, D. C., Citrin, K. M., Barber, A. T., Park, Y., Kim, J. D., Samsa, L. A., Kim, J., Liu, J., Jin, S. W., & Bautch, V. L. (2016). Notch regulates BMP responsiveness and lateral branching in vessel networks via SMAD6. Nature Communications, 7, [13247]. https://doi.org/10.1038/ncomms13247

@article{0530a3ace7274c7abb21c061e322658a,

title = "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.",

author = "Mouillesseaux, {Kevin P.} and Wiley, {David S.} and Saunders, {Lauren M.} and Wylie, {Lyndsay A.} and Kushner, {Erich J.} and Chong, {Diana C.} and Citrin, {Kathryn M.} and Barber, {Andrew T.} and Youngsook Park and Kim, {Jun Dae} and Samsa, {Leigh Ann} and Jongmin Kim and Jiandong Liu and Jin, {Suk Won} and Bautch, {Victoria L.}",

note = "Funding Information: We thank Bautch lab members for constructive discussion and input, and Drs Andrew Dudley and Frank Conlon for comments on the manuscript. This work was supported by NIH grants HL43174 and HL116719 (V.L.B.); GIST Research Institute (GRI), Cell Logistics Research Center, National Research Foundation (NRF-2016R1A5A1007318) of Korea and NIH grants HL090960 and HL114820 to S.W.J.; the NRF of Korea (NRF-2013R1A1A1057591) to J.K.; an NIH NRSA (F32HL123264-02) to K.P.M.; and AHA Predoctoral Fellowship (10PRE3290010) to D.S.W. We also thank Michelle Ortwine and the UNC Zebrafish Aquaculture Core Facility for excellent care of adult fish and the use of microinjection facilities. Publisher Copyright: {\textcopyright} The Author(s) 2016.",

year = "2016",

month = nov,

day = "11",

doi = "10.1038/ncomms13247",

language = "English (US)",

volume = "7",

journal = "Nat Commun",

issn = "2041-1723",

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T1 - Notch regulates BMP responsiveness and lateral branching in vessel networks via SMAD6

AU - Mouillesseaux, Kevin P.

AU - Wiley, David S.

AU - Saunders, Lauren M.

AU - Wylie, Lyndsay A.

AU - Kushner, Erich J.

AU - Chong, Diana C.

AU - Citrin, Kathryn M.

AU - Barber, Andrew T.

AU - Park, Youngsook

AU - Kim, Jun Dae

AU - Samsa, Leigh Ann

AU - Kim, Jongmin

AU - Liu, Jiandong

AU - Jin, Suk Won

AU - Bautch, Victoria L.

N1 - Funding Information: We thank Bautch lab members for constructive discussion and input, and Drs Andrew Dudley and Frank Conlon for comments on the manuscript. This work was supported by NIH grants HL43174 and HL116719 (V.L.B.); GIST Research Institute (GRI), Cell Logistics Research Center, National Research Foundation (NRF-2016R1A5A1007318) of Korea and NIH grants HL090960 and HL114820 to S.W.J.; the NRF of Korea (NRF-2013R1A1A1057591) to J.K.; an NIH NRSA (F32HL123264-02) to K.P.M.; and AHA Predoctoral Fellowship (10PRE3290010) to D.S.W. We also thank Michelle Ortwine and the UNC Zebrafish Aquaculture Core Facility for excellent care of adult fish and the use of microinjection facilities. Publisher Copyright: © The Author(s) 2016.

PY - 2016/11/11

Y1 - 2016/11/11

N2 - 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.

AB - 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.

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JO - Nat Commun

JF - Nat Commun

SN - 2041-1723

M1 - 13247

ER -

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

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