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

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Alk1 and Alk5 inhibition by Nrp1 controls vascular sprouting downstream of Notch.
Nature Communications ( IF 14.7 ) Pub Date : 2015-Jun-17 , DOI: 10.1038/ncomms8264
Irene Maria Aspalter ₁ , Emma Gordon ₂ , Alexandre Dubrac ₂ , Anan Ragab ₁ , Jarek Narloch ₃ , Pedro Vizán _{4,

5} , Ilse Geudens ₆ , Russell Thomas Collins _{1,

7} , Claudio Areias Franco ₁ , Cristina Luna Abrahams ₈ , Gavin Thurston ₈ , Marcus Fruttiger ₉ , Ian Rosewell ₃ , Anne Eichmann _{2,

10,

11} , Holger Gerhardt _{1,

6,

7}

Affiliation

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

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.

中文翻译：

Nrp1对Alk1和Alk5的抑制控制了Notch下游的血管发芽。

发芽的血管生成驱动健康和患病组织中的血管生长。Vegf 和 Dll4/Notch 信号在负反馈回路中协作，该回路指定内皮尖端和茎细胞，以确保足够的血管分支和功能。当前的概念假定当 Notch 不活跃时，内皮细胞默认为尖端细胞表型。在这里，我们发现需要积极抑制茎细胞表型以允许尖端细胞形成。我们证明这是神经纤毛蛋白-1 (Nrp1) 的关键内皮功能，它通过限制 Alk1 和 Alk5 激活 Smad2/3 来抑制茎细胞表型。Notch 下调 Nrp1，从而减轻对 Alk1 和 Alk5 的抑制，从而驱动茎细胞行为。从概念上讲，

更新日期：2015-06-19

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