10.6084/M9.FIGSHARE.C.6252757
Yan Xue
Yan
Xue
Nantong University
Xueting Wang
Xueting
Wang
Nantong University
Baolan Wan
Baolan
Wan
Nantong University
Dongzhi Wang
Dongzhi
Wang
Affiliated Hospital of Nantong University
Meiqi Li
Meiqi
Li
Nantong University
Kang Cheng
Kang
Cheng
Nantong University
Qianqian Luo
Qianqian
Luo
Nantong University
Dan Wang
Dan
Wang
Nantong University
Yapeng Lu
Yapeng
Lu
Nantong University
Li Zhu
Li
Zhu
Nantong University
Caveolin-1 accelerates hypoxia-induced endothelial dysfunction in high-altitude cerebral edema
Abstract Background High-altitude cerebral edema (HACE) is a serious and potentially fatal brain injury that is caused by acute hypobaric hypoxia (HH) exposure. Vasogenic edema is the main pathological factor of this condition. Hypoxia-induced disruptions of tight junctions in the endothelium trigger blood‒brain barrier (BBB) damage and induce vasogenic edema. Nuclear respiratory factor 1 (NRF1) acts as a major regulator of hypoxia-induced endothelial cell injury, and caveolin-1 (CAV-1) is upregulated as its downstream gene in hypoxic endothelial cells. This study aimed to investigate whether CAV-1 is involved in HACE progression and the underlying mechanism. Methods C57BL/6 mice were exposed to HH (7600 m above sea level) for 24 h, and BBB injury was assessed by brain water content, Evans blue staining and FITC-dextran leakage. Immunofluorescence, transmission electron microscope, transendothelial electrical resistance (TEER), transcytosis assays, and western blotting were performed to confirm the role and underlying mechanism of CAV-1 in the disruption of tight junctions and BBB permeability. Mice or bEnd.3 cells were pretreated with MβCD, a specific blocker of CAV-1, and the effect of CAV-1 on claudin-5 internalization under hypoxic conditions was detected by immunofluorescence, western blotting, and TEER. The expression of NRF1 was knocked down, and the regulation of CAV-1 by NRF1 under hypoxic conditions was examined by qPCR, western blotting, and immunofluorescence. Results The BBB was severely damaged and was accompanied by a significant loss of vascular tight junction proteins in HACE mice. CAV-1 was significantly upregulated in endothelial cells, and claudin-5 explicitly colocalized with CAV-1. During the in vitro experiments, hypoxia increased cell permeability, CAV-1 expression, and claudin-5 internalization and downregulated tight junction proteins. Simultaneously, hypoxia induced the upregulation of CAV-1 by activating NRF1. Blocking CAV-1-mediated intracellular transport improved the integrity of TJs in hypoxic endothelial cells and effectively inhibited the increase in BBB permeability and brain water content in HH animals. Conclusions Hypoxia upregulated CAV-1 transcription via the activation of NRF1 in endothelial cells, thus inducing the internalization and autophagic degradation of claudin-5. These effects lead to the destruction of the BBB and trigger HACE. Therefore, CAV-1 may be a potential therapeutic target for HACE. Video abstract
Biochemistry
Medicine
Microbiology
Cell Biology
Molecular Biology
Physiology
Chemical Sciences not elsewhere classified
Ecology
Immunology
Developmental Biology
Cancer
figshare
2022
2022-10-18
2022-10-18
Collection
CC BY 4.0