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

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

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