Non-canonical Wnt signalling modulates the endothelial shear stress flow sensor in vascular remodelling.
Non-canonical Wnt signalling modulates the endothelial shear stress flow sensor in vascular remodelling.
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DOI：
10.7554/elife.07727
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发表时间：
2016-02-04
期刊：
影响因子：
7.7
通讯作者：
Gerhardt H
中科院分区：
文献类型：
--
作者：
Franco CA;Jones ML;Bernabeu MO;Vion AC;Barbacena P;Fan J;Mathivet T;Fonseca CG;Ragab A;Yamaguchi TP;Coveney PV;Lang RA;Gerhardt H
内皮细胞对发育和血管稳态中的分子和物理力作出反应。内皮细胞对血流诱导的剪切反应的失调被认为是心血管疾病包括动脉粥样硬化的许多方面的原因。然而，分子信号和剪切介导的物理力如何整合以调节血管模式却知之甚少。在这里，我们表明，内皮非经典Wnt信号调节内皮细胞的敏感性剪切力。Wnt 5a/Wnt 11的缺失使内皮细胞对剪切更敏感，导致在较低剪切水平下的轴向极化和逆流动迁移。在整个血管网络中的流动建模和极性分析的集成表明，在动脉，静脉，毛细血管和原始发芽前沿中实现了不同的极化。总的来说，我们的数据表明，非经典的Wnt信号通过降低内皮剪切敏感性来稳定血管网络的形成，从而在原始神经丛中普遍存在的低流量条件下保持血管开放。DOI：http://dx.doi.org/10.7554/eLife.07727.001血管在生长和发育中起着至关重要的作用，因为它们运输许多帮助细胞生存的重要分子。在人的一生中，作用在血管上的力有助于重塑血管网络，以确保血液到达身体需要它的部位。例如，血液在血管内部排列的内皮细胞表面的运动对细胞施加了一种称为“剪切应力”的力。内皮细胞通过改变它们的形状、基因活性模式和内部组织（称为它们的极性）来响应和适应压力。目前还不完全清楚作用在内皮细胞上的力如何帮助重塑血管网络。Franco等人现在已经研究了称为非经典Wnt信号传导的信号传导途径如何影响小鼠血管的重塑，并发现该途径稳定了血管之间的现有连接。通过基因工程小鼠缺乏Wnt 5a和Wnt 11蛋白质来破坏非经典Wnt信号传导，增加了内皮细胞对剪切应力的敏感性。然后，Franco等人建立了一个计算机模型，模拟血管网络中的血流和内皮细胞极性;这使他们能够测量复杂血管网络中内皮细胞对血流的反应。然后，该模型用于显示缺乏非经典Wnt信号传导的内皮细胞能够在较低水平的剪切应力下重新定向并逆血流方向极化。因此，非经典Wnt信号传导有助于提高剪切应力的阈值，高于该阈值内皮细胞改变其性质。现在需要进一步的工作来确定非经典Wnt信号传导如何干扰内皮细胞感知剪切应力水平的能力。DOI：http://dx.doi.org/10.7554/eLife.07727.002网站
Endothelial cells respond to molecular and physical forces in development and vascular homeostasis. Deregulation of endothelial responses to flow-induced shear is believed to contribute to many aspects of cardiovascular diseases including atherosclerosis. However, how molecular signals and shear-mediated physical forces integrate to regulate vascular patterning is poorly understood. Here we show that endothelial non-canonical Wnt signalling regulates endothelial sensitivity to shear forces. Loss of Wnt5a/Wnt11 renders endothelial cells more sensitive to shear, resulting in axial polarization and migration against flow at lower shear levels. Integration of flow modelling and polarity analysis in entire vascular networks demonstrates that polarization against flow is achieved differentially in artery, vein, capillaries and the primitive sprouting front. Collectively our data suggest that non-canonical Wnt signalling stabilizes forming vascular networks by reducing endothelial shear sensitivity, thus keeping vessels open under low flow conditions that prevail in the primitive plexus. DOI: http://dx.doi.org/10.7554/eLife.07727.001 Blood vessels play an essential role in growth and development as they transport many important molecules that help cells to survive. Throughout life, the forces that act on the blood vessels help to remodel the vessel network to ensure that blood gets to the parts of the body that need it. For example, the movement of blood across the surface of the endothelial cells that line the inside of the blood vessels applies a force called “shear stress” to the cells. The endothelial cells respond and adapt to the stress by altering their shape, patterns of gene activity and internal organization (known as their polarity). It was not fully understood exactly how the forces acting on endothelial cells help to remodel the blood vessel network. Franco et al. have now investigated how a signalling pathway known as non-canonical Wnt signalling affects the remodelling of blood vessels in mice, and found that this pathway stabilizes existing connections between vessels. Disrupting non-canonical Wnt signalling, by genetically engineering mice to lack proteins called Wnt5a and Wnt11, increased the sensitivity of endothelial cells to shear stress. Franco et al. then built a computer model that simulates blood flow and endothelial cell polarity in a network of blood vessels; this enabled them to measure the endothelial cells’ response to blood flow in complex vascular networks. The model was then used to show that endothelial cells lacking non-canonical Wnt signalling are able to reorient and become polarized against the direction of blood flow at lower levels of shear stress. Thus, non-canonical Wnt signalling helps to raise the threshold of shear stress above which endothelial cells change their properties. Further work is now needed to identify how non-canonical Wnt signalling interferes with the ability of the endothelial cells to sense shear stress levels. DOI: http://dx.doi.org/10.7554/eLife.07727.002