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

Authors

  • I.M. Aspalter
  • E. Gordon
  • A. Dubrac
  • A. Ragab
  • J. Narloch
  • P. Vizán
  • I. Geudens
  • R.T. Collins
  • C.A. Franco
  • C.L. Abrahams
  • G. Thurston
  • M. Fruttiger
  • I. Rosewell
  • A. Eichmann
  • H. Gerhardt

Journal

  • Nature Communications

Citation

  • Nat Commun 6: 7264

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-{beta}/BMP signalling.


DOI

doi:10.1038/ncomms8264