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

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

Author information

1
Vascular Biology Laboratory, London Research Institute, Cancer Research UK, London WC2A 3LY, UK.
2
Yale Cardiovascular Research Center, Yale University School of Medicine, New Haven, Connecticut 06510, USA.
3
Transgenic Services, London Research Institute-Clare Hall Laboratories, Cancer Research UK, Potters Bar EN6 3LD, UK.
4
Developmental Signalling Laboratory, London Research Institute, Cancer Research UK, London WC2A 3LY, UK.
5
Epigenetic Events in Cancer, Centre for Genomic Regulation and Universitat Pompeu Fabra, Barcelona 080003, Spain.
6
Vascular Patterning Laboratory, Vesalius Research Center, VIB, KU Leuven B-3000, Belgium.
7
Max-Delbrück-Center for Molecular Medicine, Robert-Rössle-Strasse 10, Berlin 13125, Germany.
8
Regeneron Pharmaceuticals, Tarrytown, New York 10591, USA.
9
UCL Institute of Ophthalmology, University College London, London EC1V 9EL, UK.
10
CIRB Collège de France, Inserm U1050, Paris 75231, France.
11
Department of Cellular and Molecular Physiology, Yale University Medical School, New Haven, Connecticut 06520, USA.

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.

PMID:
26081042
PMCID:
PMC4557308
DOI:
10.1038/ncomms8264
[Indexed for MEDLINE]
Free PMC Article

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