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

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Item Type:Article
Title:Alk1 and Alk5 inhibition by Nrp1 controls vascular sprouting downstream of Notch
Creators Name:Aspalter, I.M. and Gordon, E. and Dubrac, A. and Ragab, A. and Narloch, J. and Vizan, P. and Geudens, I. and Collins, R.T. and Franco, C.A. and Abrahams, C.L. and Thurston, G. and Fruttiger, M. and Rosewell, I. and Eichmann, A. and Gerhardt, H.
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.
Keywords:Growth Differentiation Factor 2, Human Umbilical Vein Endothelial Cells, Intracellular Signaling Peptides and Proteins, Membrane Proteins, Neuropilin-1, Notch Receptors, Phenotype, Protein-Serine-Threonine Kinases, Smad2 Protein, Smad3 Protein, Transforming Growth Factor {beta} Receptors, Type I Activin Receptors, Vascular Endothelium, Animals, Mice
Source:Nature Communications
ISSN:2041-1723
Publisher:Nature Publishing Group (U.K.)
Volume:6
Page Range:7264
Date:17 June 2015
Official Publication:https://doi.org/10.1038/ncomms8264
PubMed:View item in PubMed

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