Institute of Neuroscience and State Key Laboratory of Neuroscience, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, China.
PLoS Biol. 2012;10(8):e1001374. doi: 10.1371/journal.pbio.1001374. Epub 2012 Aug 14.
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.
脑血脉管系统由高度分支的血管网络组成，该网络专门为满足其生理功能而定制。脑脉管系统是如何形成的一直令生物学家着迷。在这里，我们报告说，斑马鱼中脑的发育中的脉管系统不仅经历血管生成，而且还经历广泛的血管修剪，这是由血流变化驱动的。这个修剪过程将最初丰富的相互连接的网状结构塑造为简化的结构。通过对受精后 1.5-7.5 天的相同斑马鱼幼虫进行体内长期连续共聚焦成像，我们发现早期形成的中脑脉管系统由许多血管环和高阶节段组成。血管修剪主要通过内皮细胞（EC）从修剪到未修剪节段的侧向迁移而不是 EC 凋亡，优先发生在形成环的节段，导致随着发育血管复杂性逐渐降低。与未修剪的节段相比，修剪的节段表现出低且可变的血流，这在修剪发生之前不可逆地进一步降低。用微珠阻塞局部阻断血流会导致血管修剪，而通过增加心跳的去甲肾上腺素来增加血流会阻碍修剪过程。此外，血管修剪的发生可以通过基于血流动力学的脉管细化数值模拟来进行预测。因此，血流变化通过 EC 的侧向迁移来驱动血管修剪，导致脉管系统的简化，并可能在发育中的大脑中有效地引导血流。
