Haemodynamics-Driven Developmental Pruning of Brain Vasculature in Zebrafish

Qi Chen,David Cai,Luan Jiang,Chun Li,Ji-Wen Bu,Jiu-Lin Du,Dan Hu,Mark Krasnow

doi:10.1371/journal.pbio.1001374

Abstract

Author SummaryAlthough 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.

Highlights

The brain comprises only 2% of body weight but receives up to about 15% of cardiac output through its blood vasculature [1]
Using ‘‘segment Strahler order’’ and ‘‘internal loop’’ number to quantify the complexity of the vascular network (Figure S4A; see [23,24]), we unexpectedly found that the weighted average order, internal loop number, and percentage of vessel segments located in internal loops all significantly decreased from 2.0 to 7.5 dpf (Figures 1F, 1G, and S5), with more than 70% of changes in these parameters occurring between 2.0 and 4.0 dpf
These findings indicate that the architecture of the midbrain vasculature undergoes substantial reduction of complexity after the initial formation of the primitive vascular network

Summary

Introduction

The brain comprises only 2% of body weight but receives up to about 15% of cardiac output through its blood vasculature [1]. Abnormalities of the brain vasculature can lead to neurological disorders, including stroke, mental retardation, and neurodegeneration [1,3,4]. The brain does not produce vascular endothelial cells (ECs), and the development of its vasculature is initiated by ingression of angiogenic sprouts from surrounding peri-neural vascular plexus [5,6]. After invading into the brain, angiogenic sprouts become connected to form functional vessel networks via some not wellidentified processes, including remodeling [2,4,7,8]. The blood-brainbarrier (BBB), which governs the exchange of material between the brain tissue and vasculature system, is subsequently formed via interactions between ECs, pericytes, astrocytes, and neurons [9,10]

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Results

Conclusion