Download Haemodynamics-driven blood vessel pruning simplifies brain

Haemodynamics-driven blood vessel pruning simplifies
brain vasculature during development
Qi Chen1, Luan Jiang1, Chun Li1, Dan Hu2, Ji-wen Bu1, Jiu-lin Du1
1. Institute of Neuroscience and State Key Laboratory of Neuroscience,
Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences,
320 Yue-Yang Road, Shanghai 200031, China
2. Institute of Natural Sciences, Shanghai Jiaotong University, 800 Dong-Chuan
Road, Shanghai 200240, China
Brain blood vasculature consists of a highly ramified vessel network that is tailored for
brain function. As the brain by itself does not produce vascular progenitor cells,
ingression of blood vessels from surrounding peri-neural vascular plexus is required for
continued development of brain vasculature. Although molecular mechanisms
responsible for the vessel ingression into the brain and the formation of the blood-brain
barrier are beginning to be elucidated, the process and its underlying mechanism by
which the three-dimensional network of brain vasculature is established during
development remain largely unknown. Here we report that the vasculature in the
zebrafish midbrain undergoes haemodynamics-driven selective pruning from an
initially exuberant interconnected meshwork to a simplified architecture that facilitates
efficient arteriovenous blood flow. Using in vivo long-term time-lapse confocal imaging
of the intact zebrafish larvae during 2.0 - 7.5 days post-fertilization, we found that the
early-formed brain vasculature consisted of many vessel segments with higher order and
vessel loops, and exhibited blood flow with low and various velocity. Vessel pruning
preferentially occurred at segments which were mainly located at vessel loops and
experienced low and various blood flow and shear stress before the initiation of pruning,
and resulted in reductions of both the average segment order and loop numbers. Local
blockade of blood flow with bead obstruction or two-photon laser ablation led to vessel
pruning, whereas increasing blood flow by noradrenergic elevation of heartbeat
impeded the pruning process. The occurrence of vessel pruning was largely predicted by
haemodynamics-based numerical simulation. During pruning, endothelial cells
associated with pruned segments underwent lateral migration to adjacent unpruned
segments. Thus, haemodynamic changes drive the simplification of the brain vascular
network by triggering endothelial cell migration-associated selective vessel pruning, a
process promoting the formation of a straightway route for blood circulation and
facilitating efficient arteriovenous blood flow.