期刊
AUTOPHAGY
卷 17, 期 10, 页码 3048-3067出版社
TAYLOR & FRANCIS INC
DOI: 10.1080/15548627.2020.1851897
关键词
Autophagy; blood-brain barrier; claudin 5; hypoxia; zebrafish
类别
资金
- National Natural Science Foundation of China [31771628, 31970777]
- Guangdong Natural Science Fund for Distinguished Young Scholars [2017A030306024]
In stroke patients, autophagy activation leads to abnormal aggregation of CLDN5 in BMECs, causing BBB breakdown. Meanwhile, autophagy also contributes to the degradation of CAV1 and aggregated CLDN5, alleviating BBB impairment.
Blood-brain barrier (BBB) disruption is a key event in triggering secondary damage to the central nervous system (CNS) under stroke, and is frequently associated with abnormal macroautophagy/autophagy in brain microvascular endothelial cells (BMECs). However, the underlying mechanism of autophagy in maintaining BBB integrity remains unclear. Here we report that in BMECs of patients suffering stroke, CLDN5 (claudin 5) abnormally aggregates in the cytosol accompanied by autophagy activation. In vivo zebrafish and in vitro cell studies reveal that BBB breakdown is partially caused by CAV1 (caveolin 1)-mediated redistribution of membranous CLDN5 into the cytosol under hypoxia. Meanwhile, autophagy is activated and contributes mainly to the degradation of CAV1 and aggregated CLDN5 in the cytosol of BMECs, therefore alleviating BBB breakdown. Blockage of autophagy by genetic methods or chemicals aggravates cytosolic aggregation of CLDN5, resulting in severer BBB impairment. These data demonstrate that autophagy functions in the protection of BBB integrity by regulating CLDN5 redistribution and provide a potential therapeutic strategy for BBB disorder-related cerebrovascular disease.
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