Bmp9 regulates Notch signaling and the temporal dynamics of angiogenesis via Lunatic Fringe

Tommaso Ristori; Raphael  Thuret; Erika  Hooker; Peter  Quicke; Sami Sanlidag; Kevin  Lanthier; Kalonji  Ntumba; Irene M.  Aspalter; Marina  Uroz; Cecilia Sahlgren; Shane P.  Herbert; Christopher S. Chen; Bruno  Larrivée; Katie Bentley

doi:10.1016/j.devcel.2026.01.006

Bmp9 regulates Notch signaling and the temporal dynamics of angiogenesis via Lunatic Fringe

Tommaso Ristori^*
, Raphael Thuret
, Erika Hooker
, Peter Quicke
, Sami Sanlidag
, Kevin Lanthier
, Kalonji Ntumba
, Irene M. Aspalter
, Marina Uroz
, Cecilia Sahlgren
, Shane P. Herbert
, Christopher S. Chen
, Bruno Larrivée^*
, Katie Bentley^*

^*Korresponderande författare för detta arbete

Forskningsoutput: Tidskriftsbidrag › Artikel › Vetenskaplig › Peer review

2 Citeringar (Scopus)

14 Nedladdningar (Pure)

Sammanfattning

Sprouting angiogenesis and blood vessel stabilization require precise coordination between endothelial cells (ECs) and pericytes. Bone Morphogenic Protein 9 (Bmp9), whose signaling through activin receptor-like kinase 1 (Alk1) is dysregulated in several diseases, was thought to regulate these processes by independently activating Notch target genes in an additive fashion with canonical Notch signaling. Here, through predictive computational modeling validated in mice, zebrafish, and human cell lines, we uncover that Bmp9 enhances Notch activity synergistically by upregulating Lunatic Fringe (Lfng) in ECs. Specifically, Bmp9-induced Lfng enhances Notch receptor activation, most strongly when Delta-like ligand 4 (Dll4) is also present. This Lfng regulation alters vessel branching by modulating the timing of EC phenotype selection and rearrangement during angiogenesis. Lfng also contributes to pericyte-driven vessel stabilization by mediating Jagged1 upregulation in Bmp9-stimulated ECs. In summary, Bmp9-upregulated Lfng enhances Dll4-Notch1 signaling in ECs and Jag1-Notch3 activation in pericytes, shaping angiogenic sprouting and stabilization outcomes.

Originalspråk	Engelska
Sidor (från-till)	837-853.e9
Tidskrift	Developmental Cell
Volym	61
Nummer	4
DOI	https://doi.org/10.1016/j.devcel.2026.01.006
Status	Publicerad - 8 apr. 2026
MoE-publikationstyp	A1 Tidskriftsartikel-refererad

Finansiering

Funding: this study was supported by the Marie Sklodowska-Curie Global Fellowship, grant number 846617 (to T.R.), and by the research program NWO Rubicon, which is (partly) financed by the Dutch Research Council (NWO), with project number 019.183EN.025 (to T.R.). The Graduate School of Åbo Akademi University and the Swedish Cultural Foundation are acknowledged for their financial support (S.S.). C.M.S. was supported by the Research Council of Finland, decision number 330411 (SignalSheets); the European Research Council (ERC); and the European Union’s Horizon 2020 research and innovation program, grant agreement number 771168 (ForceMorph). M.U. was supported by an EMBO long-term fellowship (EMBO ALTF811-2018), the Center for Multiscale & Translational Mechanobiology at Boston University, and an AHA postdoctoral fellowship (828475). M.U. and C.S.C. were supported by NIH (EB00262 and HL147585). S.P.H. was supported by the Wellcome Trust (219500/Z/19/Z) and the British Heart Foundation (PG/18/67/33891). B.L. was supported by the Canadian Institutes of Health Research (FRN 363540) and the Natural Sciences and Engineering Research Council of Canada (RGPIN/05222-2018). K.B., P.Q., and I.M.A. were supported by the Francis Crick Institute, which receives its core funding from Cancer Research UK (FC001751), the UK Medical Research Council (FC001751), and the Wellcome Trust (FC001751).

Åtkomst av dokument

10.1016/j.devcel.2026.01.006Licens: CC BY

2026 Bmp9 regulates Notch signaling and the temporal dynamics of angiogenesis via Lunatic Fringe (Ristori et al.)Slutlig publicerad version, 11,4 MBLicens: CC BY

https://urn.fi/URN:NBN:fi-fe2026050136907

SignalSheets: Multilayer mechanosignalling in vascular homeostasis
Sahlgren, C. (Ansvarig forskare)
01/09/20 → 31/08/24
Projekt: Finlands Akademi/Övriga Forskningsråd
ForceMorph: The integration of cell signalling and mechanical forces in vascular morphology
Sahlgren, C. (Ansvarig forskare)
European Research Council
01/03/18 → 31/08/23
Projekt: EU

Citera det här

Ristori, T., Thuret , R., Hooker, E., Quicke, P., Sanlidag, S., Lanthier, K., Ntumba, K., Aspalter, I. M., Uroz, M., Sahlgren, C., Herbert , S. P., Chen, C. S., Larrivée, B., & Bentley, K. (2026). Bmp9 regulates Notch signaling and the temporal dynamics of angiogenesis via Lunatic Fringe. Developmental Cell, 61(4), 837-853.e9. https://doi.org/10.1016/j.devcel.2026.01.006

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title = "Bmp9 regulates Notch signaling and the temporal dynamics of angiogenesis via Lunatic Fringe",

abstract = "Sprouting angiogenesis and blood vessel stabilization require precise coordination between endothelial cells (ECs) and pericytes. Bone Morphogenic Protein 9 (Bmp9), whose signaling through activin receptor-like kinase 1 (Alk1) is dysregulated in several diseases, was thought to regulate these processes by independently activating Notch target genes in an additive fashion with canonical Notch signaling. Here, through predictive computational modeling validated in mice, zebrafish, and human cell lines, we uncover that Bmp9 enhances Notch activity synergistically by upregulating Lunatic Fringe (Lfng) in ECs. Specifically, Bmp9-induced Lfng enhances Notch receptor activation, most strongly when Delta-like ligand 4 (Dll4) is also present. This Lfng regulation alters vessel branching by modulating the timing of EC phenotype selection and rearrangement during angiogenesis. Lfng also contributes to pericyte-driven vessel stabilization by mediating Jagged1 upregulation in Bmp9-stimulated ECs. In summary, Bmp9-upregulated Lfng enhances Dll4-Notch1 signaling in ECs and Jag1-Notch3 activation in pericytes, shaping angiogenic sprouting and stabilization outcomes.",

keywords = "Bone Morphogenic Protein 9, Lunatic Fringe, Notch signaling, Activin receptor-like kinase 1, angiogenesis, computational modeling, endothelial cells, pericytes, hereditary hemorrhagic telangiectasia",

author = "Tommaso Ristori and Raphael Thuret and Erika Hooker and Peter Quicke and Sami Sanlidag and Kevin Lanthier and Kalonji Ntumba and Aspalter, \{Irene M.\} and Marina Uroz and Cecilia Sahlgren and Herbert, \{Shane P.\} and Chen, \{Christopher S.\} and Bruno Larriv{\'e}e and Katie Bentley",

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doi = "10.1016/j.devcel.2026.01.006",

language = "English",

volume = "61",

pages = "837--853.e9",

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T1 - Bmp9 regulates Notch signaling and the temporal dynamics of angiogenesis via Lunatic Fringe

AU - Ristori, Tommaso

AU - Thuret , Raphael

AU - Hooker, Erika

AU - Quicke, Peter

AU - Sanlidag, Sami

AU - Lanthier, Kevin

AU - Ntumba, Kalonji

AU - Aspalter, Irene M.

AU - Uroz, Marina

AU - Sahlgren, Cecilia

AU - Herbert , Shane P.

AU - Chen, Christopher S.

AU - Larrivée, Bruno

AU - Bentley, Katie

PY - 2026/4/8

Y1 - 2026/4/8

N2 - Sprouting angiogenesis and blood vessel stabilization require precise coordination between endothelial cells (ECs) and pericytes. Bone Morphogenic Protein 9 (Bmp9), whose signaling through activin receptor-like kinase 1 (Alk1) is dysregulated in several diseases, was thought to regulate these processes by independently activating Notch target genes in an additive fashion with canonical Notch signaling. Here, through predictive computational modeling validated in mice, zebrafish, and human cell lines, we uncover that Bmp9 enhances Notch activity synergistically by upregulating Lunatic Fringe (Lfng) in ECs. Specifically, Bmp9-induced Lfng enhances Notch receptor activation, most strongly when Delta-like ligand 4 (Dll4) is also present. This Lfng regulation alters vessel branching by modulating the timing of EC phenotype selection and rearrangement during angiogenesis. Lfng also contributes to pericyte-driven vessel stabilization by mediating Jagged1 upregulation in Bmp9-stimulated ECs. In summary, Bmp9-upregulated Lfng enhances Dll4-Notch1 signaling in ECs and Jag1-Notch3 activation in pericytes, shaping angiogenic sprouting and stabilization outcomes.

AB - Sprouting angiogenesis and blood vessel stabilization require precise coordination between endothelial cells (ECs) and pericytes. Bone Morphogenic Protein 9 (Bmp9), whose signaling through activin receptor-like kinase 1 (Alk1) is dysregulated in several diseases, was thought to regulate these processes by independently activating Notch target genes in an additive fashion with canonical Notch signaling. Here, through predictive computational modeling validated in mice, zebrafish, and human cell lines, we uncover that Bmp9 enhances Notch activity synergistically by upregulating Lunatic Fringe (Lfng) in ECs. Specifically, Bmp9-induced Lfng enhances Notch receptor activation, most strongly when Delta-like ligand 4 (Dll4) is also present. This Lfng regulation alters vessel branching by modulating the timing of EC phenotype selection and rearrangement during angiogenesis. Lfng also contributes to pericyte-driven vessel stabilization by mediating Jagged1 upregulation in Bmp9-stimulated ECs. In summary, Bmp9-upregulated Lfng enhances Dll4-Notch1 signaling in ECs and Jag1-Notch3 activation in pericytes, shaping angiogenic sprouting and stabilization outcomes.

KW - Bone Morphogenic Protein 9

KW - Lunatic Fringe

KW - Notch signaling

KW - Activin receptor-like kinase 1

KW - angiogenesis

KW - computational modeling

KW - endothelial cells

KW - pericytes

KW - hereditary hemorrhagic telangiectasia

U2 - 10.1016/j.devcel.2026.01.006

DO - 10.1016/j.devcel.2026.01.006

M3 - Article

SN - 1534-5807

VL - 61

SP - 837-853.e9

JO - Developmental Cell

JF - Developmental Cell

IS - 4

ER -

Bmp9 regulates Notch signaling and the temporal dynamics of angiogenesis via Lunatic Fringe

Sammanfattning

Finansiering

Åtkomst av dokument

Fingeravtryck

Projekt

SignalSheets: Multilayer mechanosignalling in vascular homeostasis

ForceMorph: The integration of cell signalling and mechanical forces in vascular morphology

Citera det här