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

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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