Haemodynamics-driven developmental pruning of brain vasculature in zebrafish.
Haemodynamics-driven developmental pruning of brain vasculature in zebrafish.
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血流动力学驱动的斑马鱼脑血管发育修剪
DOI：
10.1371/journal.pbio.1001374
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发表时间：
2012
期刊：
影响因子：
9.8
通讯作者：
Du JL
中科院分区：
文献类型：
--
作者：
Chen Q;Jiang L;Li C;Hu D;Bu JW;Cai D;Du JL
这项在斑马鱼体内进行的延时成像研究揭示了脑血流的变化如何通过内皮细胞迁移驱动血管修剪，以及修剪如何导致发育过程中脑血管系统的简化。虽然大脑仅占体重的2%，但它接收15%的心输出量，并消耗通过其血管输送的全身氧气的20%。脑血管系统由高度分支的血管网络组成，该血管网络被定制为有效地将氧气和营养物质输送到每个脑区域。然而，人们对脑血管系统如何发育知之甚少。使用在体内长期序列共聚焦成像的斑马鱼幼虫，我们分析了这一过程，发现发展中的中脑血管不仅经历血管生长，但也血流驱动的血管修剪。我们发现，血管修剪优先发生在环形血管段通过内皮细胞迁移到相邻的未修剪的部分，随着时间的推移，这种血管修剪降低了早期原始中脑血管的复杂性。我们还观察到，修剪的血管段表现出更低和更可变的血流比未修剪的段，血流的局部阻塞触发血管修剪。相比之下，血流量的增加会损害血管修剪。最后，我们表明，修剪事件可以预测使用基于血液动力学的数学模型的中脑血管。这些研究结果表明，在发展过程中存在的脑血管修剪，并提供了新的见解脑血管细化的血液动力学的作用。脑血管系统由高度分叉的血管网络组成，其被定制以满足其生理功能。脑血管系统是如何形成的一直是生物学家们所着迷的。在这里，我们报告说，发展中的血管系统在斑马鱼中脑不仅经历血管生成，但也广泛的血管修剪，这是由血流的变化驱动。这个修剪过程将最初旺盛的互连网络塑造成一个简化的架构。利用在体长期连续共聚焦成像的同一斑马鱼幼虫在1.5-7.5天受精后，我们发现，早期形成的中脑血管由许多血管环路和高阶段。血管修剪优先发生在环形成段通过一个过程，主要涉及横向迁移的内皮细胞（EC）从修剪到unpruned段，而不是EC凋亡，导致血管系统的复杂性逐渐减少与发展。与未修剪的相比，修剪的片段表现出低的和可变的血流量，进一步减少不可逆的修剪开始之前。微珠阻塞局部阻断血流导致血管修剪，而心跳的去甲肾上腺素能升高增加血流阻碍了修剪过程。此外，血管修剪的发生在很大程度上可以通过基于血液动力学的血管细化的数值模拟来预测。因此，血流的变化通过EC的侧向迁移驱动血管修剪，导致血管系统的简化和发育中大脑中血流的可能有效路由。
This in vivo time-lapse imaging study in zebrafish reveals how changes to brain blood flow drive vessel pruning via endothelial cell migration, and how pruning leads to the simplification of the brain vasculature during development. Although the brain comprises only 2% of body weight, it receives 15% of cardiac output and consumes 20% of total body oxygen delivered through its blood vasculature. The brain blood vasculature consists of a highly branched vessel network that is tailored to efficiently deliver oxygen and nutrients to each brain region. However, little is known about how the brain vasculature develops. Using in vivo long-term serial confocal imaging of zebrafish larvae, we analyze this process and find that the developing midbrain vasculature undergoes not only vessel growth but also blood flow-driven vessel pruning. We show that vessel pruning occurs preferentially at loop-shaped vessel segments via the migration of endothelial cells to adjacent unpruned segments; over time, such vessel pruning reduces the complexity of the early primitive midbrain vasculature. We also observe that pruned vessel segments exhibit a lower and more variable blood flow than do unpruned segments and that the local blocking of blood flow triggers vessel pruning. By contrast, increases in blood flow impair vessel pruning. Finally, we show that pruning events can be predicted using a haemodynamics based mathematical model of the midbrain vasculature. These findings demonstrate the existence of brain vessel pruning during development and provide novel insights into the role of haemodynamics in brain vascular refinement. The brain blood vasculature consists of a highly ramified vessel network that is tailored to meet its physiological functions. How the brain vasculature is formed has long been fascinating biologists. Here we report that the developing vasculature in the zebrafish midbrain undergoes not only angiogenesis but also extensive vessel pruning, which is driven by changes in blood flow. This pruning process shapes the initial exuberant interconnected meshwork into a simplified architecture. Using in vivo long-term serial confocal imaging of the same zebrafish larvae during 1.5–7.5 d post-fertilization, we found that the early formed midbrain vasculature consisted of many vessel loops and higher order segments. Vessel pruning occurred preferentially at loop-forming segments via a process mainly involving lateral migration of endothelial cells (ECs) from pruned to unpruned segments rather than EC apoptosis, leading to gradual reduction in the vasculature complexity with development. Compared to unpruned ones, pruned segments exhibited a low and variable blood flow, which further decreased irreversibly prior to the onset of pruning. Local blockade of blood flow with micro-bead obstruction led to vessel pruning, whereas increasing blood flow by noradrenergic elevation of heartbeat impeded the pruning process. Furthermore, the occurrence of vessel pruning could be largely predicted by haemodynamics-based numerical simulation of vasculature refinement. Thus, changes of blood flow drive vessel pruning via lateral migration of ECs, leading to the simplification of the vasculature and possibly efficient routing of blood flow in the developing brain.
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DOI：
10.1073/pnas.1019761108
发表时间：
2011-02-15
影响因子：
11.1
作者：
Anderson, Keith D.;Pan, Li;Gale, Nicholas W.
通讯作者：
Gale, Nicholas W.
影响因子：
5.3
作者：
Itoh, RE;Kurokawa, K;Matsuda, M
通讯作者：
Matsuda, M
DOI：
10.1038/nrm3176
发表时间：
2011-08-23
期刊：
Nature reviews. Molecular cell biology
影响因子：
--
作者：
通讯作者：
--
影响因子：
4.6
作者：
Corti, Paola;Young, Sarah;Roman, Beth L.
通讯作者：
Roman, Beth L.
影响因子：
4.6
作者：
Fujita, Misato;Cha, Young R.;Weinstein, Brant M.
通讯作者：
Weinstein, Brant M.