Alk1 and Alk5 inhibition by Nrp1 controls vascular sprouting downstream of Notch.
Alk1 and Alk5 inhibition by Nrp1 controls vascular sprouting downstream of Notch.
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DOI：
10.1038/ncomms8264
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发表时间：
2015-06-17
影响因子：
16.6
通讯作者：
Gerhardt H
中科院分区：
文献类型：
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作者：
Aspalter IM;Gordon E;Dubrac A;Ragab A;Narloch J;Vizán P;Geudens I;Collins RT;Franco CA;Abrahams CL;Thurston G;Fruttiger M;Rosewell I;Eichmann A;Gerhardt H
萌芽的血管生成驱动健康和患病组织中的血管生长。VEGF和Dll 4/Notch信号传导在负反馈回路中合作，该负反馈回路指定内皮尖端和柄细胞以确保足够的血管分支和功能。目前的概念认为，当Notch失活时，内皮细胞默认为尖端细胞表型。在这里，我们确定，而不是茎细胞表型需要积极抑制，让尖细胞的形成。我们发现这是神经纤毛蛋白-1（Nrp 1）的一个关键内皮功能，它通过限制Alk 1和Alk 5激活Smad 2/3来抑制茎细胞表型。Notch下调Nrp 1，从而解除Alk 1和Alk 5的抑制，从而驱动茎细胞行为。从概念上讲，我们的工作表明，由Dll 4/Notch的横向反馈回路建立的相邻内皮细胞之间的异质性利用Nrp 1水平作为支点，这反过来又建立了对TGF-β/BMP信号传导的差异反应性。 Notch信号对于将血管生成萌芽细胞组织成前导“尖端”和拖尾“柄”细胞至关重要。在这里，作者表明内皮神经纤毛蛋白-1定量抑制TGF-β/BMP信号传导，解释了Notch介导的神经纤毛蛋白-1调节如何指定内皮尖端和柄细胞。
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. Notch signals are crucial for organization of angiogenic sprouting cells into the leading ‘tip' and trailing ‘stalk' cells. Here the authors show that endothelial neuropilin-1 quantitatively inhibits TGF-β/BMP signalling, explaining how Notch-mediated regulation of neuropilin-1 specifies endothelial tip and stalk cells.