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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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