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Caveolin-1 accelerates hypoxia-induced endothelial dysfunction in high-altitude cerebral edema
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‒...
Autores principales: | , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
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BioMed Central
2022
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9575296/ https://www.ncbi.nlm.nih.gov/pubmed/36253854 http://dx.doi.org/10.1186/s12964-022-00976-3 |
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author | Xue, Yan Wang, Xueting Wan, Baolan Wang, Dongzhi Li, Meiqi Cheng, Kang Luo, Qianqian Wang, Dan Lu, Yapeng Zhu, Li |
author_facet | Xue, Yan Wang, Xueting Wan, Baolan Wang, Dongzhi Li, Meiqi Cheng, Kang Luo, Qianqian Wang, Dan Lu, Yapeng Zhu, Li |
author_sort | Xue, Yan |
collection | PubMed |
description | 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. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s12964-022-00976-3. |
format | Online Article Text |
id | pubmed-9575296 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
publisher | BioMed Central |
record_format | MEDLINE/PubMed |
spelling | pubmed-95752962022-10-18 Caveolin-1 accelerates hypoxia-induced endothelial dysfunction in high-altitude cerebral edema Xue, Yan Wang, Xueting Wan, Baolan Wang, Dongzhi Li, Meiqi Cheng, Kang Luo, Qianqian Wang, Dan Lu, Yapeng Zhu, Li Cell Commun Signal Research 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. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s12964-022-00976-3. BioMed Central 2022-10-17 /pmc/articles/PMC9575296/ /pubmed/36253854 http://dx.doi.org/10.1186/s12964-022-00976-3 Text en © The Author(s) 2022 https://creativecommons.org/licenses/by/4.0/Open AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) . The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/ (https://creativecommons.org/publicdomain/zero/1.0/) ) applies to the data made available in this article, unless otherwise stated in a credit line to the data. |
spellingShingle | Research Xue, Yan Wang, Xueting Wan, Baolan Wang, Dongzhi Li, Meiqi Cheng, Kang Luo, Qianqian Wang, Dan Lu, Yapeng Zhu, Li Caveolin-1 accelerates hypoxia-induced endothelial dysfunction in high-altitude cerebral edema |
title | Caveolin-1 accelerates hypoxia-induced endothelial dysfunction in high-altitude cerebral edema |
title_full | Caveolin-1 accelerates hypoxia-induced endothelial dysfunction in high-altitude cerebral edema |
title_fullStr | Caveolin-1 accelerates hypoxia-induced endothelial dysfunction in high-altitude cerebral edema |
title_full_unstemmed | Caveolin-1 accelerates hypoxia-induced endothelial dysfunction in high-altitude cerebral edema |
title_short | Caveolin-1 accelerates hypoxia-induced endothelial dysfunction in high-altitude cerebral edema |
title_sort | caveolin-1 accelerates hypoxia-induced endothelial dysfunction in high-altitude cerebral edema |
topic | Research |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9575296/ https://www.ncbi.nlm.nih.gov/pubmed/36253854 http://dx.doi.org/10.1186/s12964-022-00976-3 |
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