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

Irene Maria Aspalter, Emma Gordon, Alexandre Dubrac, Anan Ragab, Jarek Narloch, Pedro Vizán, Ilse Geudens, Russell Thomas Collins, Claudio Areias Franco, Cristina Luna Abrahams, Gavin Thurston, Marcus Fruttiger, Ian Rosewell, Anne Eichmann () and Holger Gerhardt ()
Additional contact information
Irene Maria Aspalter: Vascular Biology Laboratory, London Research Institute, Cancer Research UK
Emma Gordon: Yale Cardiovascular Research Center, Yale University School of Medicine
Alexandre Dubrac: Yale Cardiovascular Research Center, Yale University School of Medicine
Anan Ragab: Vascular Biology Laboratory, London Research Institute, Cancer Research UK
Jarek Narloch: Transgenic Services, London Research Institute—Clare Hall Laboratories, Cancer Research UK
Pedro Vizán: Developmental Signalling Laboratory, London Research Institute, Cancer Research UK
Ilse Geudens: Vascular Patterning Laboratory, Vesalius Research Center, VIB
Russell Thomas Collins: Vascular Biology Laboratory, London Research Institute, Cancer Research UK
Claudio Areias Franco: Vascular Biology Laboratory, London Research Institute, Cancer Research UK
Cristina Luna Abrahams: Regeneron Pharmaceuticals
Gavin Thurston: Regeneron Pharmaceuticals
Marcus Fruttiger: UCL Institute of Ophthalmology, University College London
Ian Rosewell: Transgenic Services, London Research Institute—Clare Hall Laboratories, Cancer Research UK
Anne Eichmann: Yale Cardiovascular Research Center, Yale University School of Medicine
Holger Gerhardt: Vascular Biology Laboratory, London Research Institute, Cancer Research UK

Nature Communications, 2015, vol. 6, issue 1, 1-13

Abstract: 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.

Date: 2015
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DOI: 10.1038/ncomms8264

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