Aspalter, Irene MariaGordon, EmmaDubrac, AlexandreRagab, AnanNarloch, JarekVizán, PedroGeudens, IlseCollins, Russell ThomasAreias Franco, ClaudioAbrahams, Cristina LunaThurston, GavinFruttiger, MarcusRosewell, IanEichmann, AnneGerhardt, Holger2023-06-262023-06-262015Aspalter IM, Gordon E, Dubrac A, Ragab A, Narloch J, Vizán P, et al. Alk1 and Alk5 inhibition by Nrp1 controls vascular sprouting downstream of Notch. Nat Commun. 2015 Jun 17;6:7264. DOI: 10.1038/ncomms82642041-1723http://hdl.handle.net/10230/57334Includes supplementary materials for the online appendix.Sprouting angiogenesis drives blood vessel growth in healthy and diseased tissues. Vegf and Dll4/Notch signalling cooperate in a negative feedback loop that specifies endothelial tip and stalk cells to ensure adequate vessel branching and function. Current concepts posit that endothelial cells default to the tip-cell phenotype when Notch is inactive. Here we identify instead that the stalk-cell phenotype needs to be actively repressed to allow tip-cell formation. We show this is a key endothelial function of neuropilin-1 (Nrp1), which suppresses the stalk-cell phenotype by limiting Smad2/3 activation through Alk1 and Alk5. Notch downregulates Nrp1, thus relieving the inhibition of Alk1 and Alk5, thereby driving stalk-cell behaviour. Conceptually, our work shows that the heterogeneity between neighbouring endothelial cells established by the lateral feedback loop of Dll4/Notch utilizes Nrp1 levels as the pivot, which in turn establishes differential responsiveness to TGF-β/BMP signalling.application/pdfengThis work is licensed under a Creative Commons Attribution 4.0 International License. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder to reproduce the material. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/Vasos sanguinisSistema cardiovascularEndoteliEndoteli vascularinfo:eu-repo/semantics/articlehttp://dx.doi.org/10.1038/ncomms8264info:eu-repo/semantics/openAccess