Haemodynamics-driven developmental pruning of brain vasculature in zebrafish

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Animals, Genetically Modified / physiology
  • Blood Flow Velocity
  • Cell Movement
  • Embryo, Nonmammalian / blood supply
  • Embryo, Nonmammalian / embryology
  • Embryo, Nonmammalian / physiology
  • Embryonic Development
  • Endothelial Cells / physiology
  • Hemodynamics*
  • Larva / physiology
  • Macrophages / physiology
  • Mesencephalon / anatomy & histology
  • Mesencephalon / blood supply*
  • Mesencephalon / physiology
  • Microscopy, Confocal / methods
  • Models, Biological
  • Neovascularization, Physiologic*
  • Zebrafish / anatomy & histology
  • Zebrafish / genetics
  • Zebrafish / physiology*

Grant support

This work was supported by grants from the National Basic Research Program of China (2012CB945101, 2011CBA00400 and 2006CB943800), Shanghai government (06dj14010, 07pj14107) and the Hundred Talents Program from Chinese Academy of Sciences. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.