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.

• Authors: Yan Xue, Xueting Wang, Baolan Wan, Dongzhi Wang, Meiqi Li, Kang Cheng, Qianqian Luo, Dan Wang, Yapeng Lu, Li Zhu
• Journal: Cell communication and signaling : CCS (Cell Commun Signal) Vol. 20 Issue 1 Pg. 160 (10 17 2022) ISSN: 1478-811X [Electronic] England
• PMID: 36253854 (Publication Type: Journal Article, Video-Audio Media, Research Support, Non-U.S. Gov't)
• Copyright: © 2022. The Author(s).

Chemical References

• Caveolin 1
• Claudin-5
• Nuclear Respiratory Factor 1
• Tight Junction Proteins
• Cav1 protein, mouse

Topics

• Animals
• Mice
• Altitude
• Blood-Brain Barrier
• Brain Edema (complications, metabolism)
• Caveolin 1 (metabolism)
• Claudin-5 (metabolism)
• Endothelial Cells (metabolism)
• Hypoxia (complications, metabolism)
• Mice, Inbred C57BL
• Nuclear Respiratory Factor 1 (metabolism)
• Tight Junction Proteins (metabolism)
• Tight Junctions (metabolism)