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

Nat Commun. 2015 Jun 17:6:7264. doi: 10.1038/ncomms8264.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Activin Receptors, Type I / metabolism*
  • Activin Receptors, Type II
  • Animals
  • Endothelium, Vascular / growth & development*
  • Growth Differentiation Factor 2 / metabolism
  • Human Umbilical Vein Endothelial Cells
  • Humans
  • Intracellular Signaling Peptides and Proteins / metabolism
  • Membrane Proteins / metabolism
  • Mice
  • Neuropilin-1 / metabolism*
  • Phenotype
  • Protein Serine-Threonine Kinases / metabolism*
  • Receptor, Transforming Growth Factor-beta Type I
  • Receptors, Notch / metabolism*
  • Receptors, Transforming Growth Factor beta / metabolism*
  • Smad2 Protein / metabolism
  • Smad3 Protein / metabolism

Substances

  • Gdf2 protein, mouse
  • Growth Differentiation Factor 2
  • Intracellular Signaling Peptides and Proteins
  • Membrane Proteins
  • Receptors, Notch
  • Receptors, Transforming Growth Factor beta
  • Smad2 Protein
  • Smad3 Protein
  • delta protein
  • Neuropilin-1
  • Protein Serine-Threonine Kinases
  • Activin Receptors, Type I
  • Activin Receptors, Type II
  • Acvrl1 protein, mouse
  • Receptor, Transforming Growth Factor-beta Type I
  • TGFBR1 protein, human
  • Tgfbr1 protein, mouse