A1 Refereed original research article in a scientific journal
Bmp9 regulates Notch signaling and the temporal dynamics of angiogenesis via Lunatic Fringe
Authors: Ristori, Tommaso; Thuret, Raphael; Hooker, Erika; Quicke, Peter; Sanlidag, Sami; Lanthier, Kevin; Ntumba, Kalonji; Aspalter, Irene M.; Uroz, Marina; Sahlgren, Cecilia M.; Herbert, Shane P.; Chen, Christopher S.; Larrivée, Bruno; Bentley, Katie
Publisher: Cell Press
Publication year: 2026
Journal: Developmental Cell
ISSN: 1534-5807
eISSN: 1878-1551
DOI: https://doi.org/10.1016/j.devcel.2026.01.006
Publication's open availability at the time of reporting: Open Access
Publication channel's open availability : Partially Open Access publication channel
Web address : https://doi.org/10.1016/j.devcel.2026.01.006
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.
Funding information in the publication:
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).
