Alk1 and Alk5 inhibition by Nrp1 controls vascular sprouting downstream of Notch

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  • dc.contributor.author Aspalter, Irene Maria
  • dc.contributor.author Gordon, Emma
  • dc.contributor.author Dubrac, Alexandre
  • dc.contributor.author Ragab, Anan
  • dc.contributor.author Narloch, Jarek
  • dc.contributor.author Vizán, Pedro
  • dc.contributor.author Geudens, Ilse
  • dc.contributor.author Collins, Russell Thomas
  • dc.contributor.author Areias Franco, Claudio
  • dc.contributor.author Abrahams, Cristina Luna
  • dc.contributor.author Thurston, Gavin
  • dc.contributor.author Fruttiger, Marcus
  • dc.contributor.author Rosewell, Ian
  • dc.contributor.author Eichmann, Anne
  • dc.contributor.author Gerhardt, Holger
  • dc.date.accessioned 2023-06-26T06:02:44Z
  • dc.date.available 2023-06-26T06:02:44Z
  • dc.date.issued 2015
  • dc.description Includes supplementary materials for the online appendix.
  • dc.description.abstract 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.
  • dc.description.sponsorship We are grateful to Dr Guido Serini for provision of Nrp1 expression constructs. We thank Dr Daniel Greif and Dr Teodelinda Mirabella (Yale University) for providing Alk5 floxed mice. We thank Dr Caroline Hill (London Research Institute, CRUK) for her invaluable scientific input and Michael Simons for critical reading of the manuscript. Furthermore, we thank Mary Ann Haskings (Transgenic Services, London Research Institute—Clare Hall Laboratories) for her help in generating chimeric mice. I.M.A. is a recipient of a DOC-fFORTE fellowship of the Austrian Academy of Sciences at the London Research Institute—Cancer Research UK. C.A.F. is supported by a EU FP7 Marie Curie Post-doctoral Fellowship. This work was supported by Cancer Research UK (H.G.), the EMBO Young Investigator Programme (H.G.), the Lister Institute of Preventive Medicine (H.G.), the ERC starting grant Reshape (311719) (H.G.), the Leducq Transatlantic Network ARTEMIS (H.G. and A.E.), NIH R01 HL 111504-02 (A.E.) and Thome Memorial Foundation (A.E.).
  • dc.format.mimetype application/pdf
  • dc.identifier.citation Aspalter 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/ncomms8264
  • dc.identifier.doi http://dx.doi.org/10.1038/ncomms8264
  • dc.identifier.issn 2041-1723
  • dc.identifier.uri http://hdl.handle.net/10230/57334
  • dc.language.iso eng
  • dc.publisher Nature Research
  • dc.relation.ispartof Nature Communications. 2015 Jun 17;6:7264
  • dc.relation.projectID info:eu-repo/grantAgreement/EC/FP7/311719
  • dc.rights This 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/
  • dc.rights.accessRights info:eu-repo/semantics/openAccess
  • dc.rights.uri http://creativecommons.org/licenses/by/4.0/
  • dc.subject.other Vasos sanguinis
  • dc.subject.other Sistema cardiovascular
  • dc.subject.other Endoteli
  • dc.subject.other Endoteli vascular
  • dc.title Alk1 and Alk5 inhibition by Nrp1 controls vascular sprouting downstream of Notch
  • dc.type info:eu-repo/semantics/article
  • dc.type.version info:eu-repo/semantics/publishedVersion

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