Haemodynamics-driven developmental pruning of brain vasculature in zebrafish

• Published in: PLoS biology 2012-08, Vol.10 (8), p.e1001374-e1001374
• Main Authors: Chen, Qi, Jiang, Luan, Li, Chun, Hu, Dan, Bu, Ji-wen, Cai, David, Du, Jiu-lin
• Format: Article
• Language: English
• Subjects: Angiogenesis; Animals; Animals, Genetically Modified - physiology; Biology; Blood Flow Velocity; Blood vessels; Brain research; Cell Movement; Central nervous system; Embryo, Nonmammalian - blood supply; Embryo, Nonmammalian - embryology; Embryo, Nonmammalian - physiology; Embryonic Development; Endothelial Cells - physiology; Experiments; Hemodynamics; Larva - physiology; Macrophages - physiology; Mathematical models; Mesencephalon - anatomy & histology; Mesencephalon - blood supply; Mesencephalon - physiology; Microscopy, Confocal - methods; Migration; Models, Biological; Neovascularization, Physiologic; Observations; Physiological aspects; Veterinary physiology; Zebra fish; Zebrafish - anatomy & histology; Zebrafish - genetics; Zebrafish - physiology
• ISSN: 1545-7885; 1544-9173; 1545-7885
• DOI: 10.1371/journal.pbio.1001374

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.