Endothelial Autophagy: an Effective Target for Radiation-induced Cerebral Capillary Damage

Xiaolin Ai,Xi Huang,Min Fan,Zengpanpan Ye,Jian Zhong,Dongmei Zhang,Xuejiao Song,Jianghong Xiao,Chengjian Zhao,Jianguo Xu,Yuqin Yao,Chao You,Huashan Shi

doi:10.1038/s41598-019-57234-9

Xiaolin Ai, Xi Huang + Show 11 more

Open Access

https://doi.org/10.1038/s41598-019-57234-9

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Abstract

Toxicity to central nervous system tissues is the common side effects for radiotherapy of brain tumor. The radiation toxicity has been thought to be related to the damage of cerebral endothelium. However, because of lacking a suitable high-resolution vivo model, cellular response of cerebral capillaries to radiation remained unclear. Here, we present the flk:eGFP transgenic zebrafish larvae as a feasible model to study the radiation toxicity to cerebral capillary. We showed that, in living zebrafish larvae, radiation could induce acute cerebral capillary shrinkage and blood-flow obstruction, resulting brain hypoxia and glycolysis retardant. Although in vivo neuron damage was also observed after the radiation exposure, further investigation found that they didn’t response to the same dosage of radiation in vitro, indicating that radiation induced neuron damage was a secondary-effect of cerebral vascular function damage. In addition, transgenic labeling and qPCR results showed that the radiation-induced acute cerebral endothelial damage was correlated with intensive endothelial autophagy. Different autophagy inhibitors could significantly alleviate the radiation-induced cerebral capillary damage and prolong the survival of zebrafish larvae. Therefore, we showed that radiation could directly damage cerebral capillary, resulting to blood flow deficiency and neuron death, which suggested endothelial autophagy as a potential target for radiation-induced brain toxicity.

Highlights

Toxicity to central nervous system tissues is the common side effects for radiotherapy of brain tumor
After comparing 3-dimensional computed tomography angiography (Fig. 1), we found that the intracranial vessels and blood-perfusion was significantly affected after the last time of radiation
Previous studies have suggested that endothelial cells were more sensitive to radiation compared with neurons and glial cells; brain injury induced by radiotherapy may be related to vascular damage[12]

Summary

Introduction

Toxicity to central nervous system tissues is the common side effects for radiotherapy of brain tumor. We present the flk:eGFP transgenic zebrafish larvae as a feasible model to study the radiation toxicity to cerebral capillary. In living zebrafish larvae, radiation could induce acute cerebral capillary shrinkage and blood-flow obstruction, resulting brain hypoxia and glycolysis retardant. We showed that radiation could directly damage cerebral capillary, resulting to blood flow deficiency and neuron death, which suggested endothelial autophagy as a potential target for radiation-induced brain toxicity. Glial and vascular compartments of the brain and may lead to molecular, cellular and functional changes[9]. Whole-brain living images of fli1a:mCherry-GFP-LC3 transgenic zebrafish larvae and q-PCR data indicated the association of endothelial autophagy with the radiation induced damage to cerebral capillary. Autophagy inhibition experiments highlighted the use of autophagy inhibitors in relieving the damage of cerebral capillaries and the subsequent effect to the neurons and glia after the radiotherapy

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