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<p>Cerebral white matter exhibits heightened susceptibility to chronic hypoperfusion. Increasing evidence implicates glial cells, notably astrocytes, in mediating chronic ischemic demyelination. To elucidate the involvement of astrocytes in ischemic white matter pathologies, we conducted an ultrastructural characterization of intracellular contents in reactive astrocytes of mice following bilateral carotid artery stenosis (BCAS), a model of chronic cerebral hypoperfusion. BCAS triggered robust activation of astrocytes, with electron-dense dark astrocytes demonstrating cytoplasmic/nuclear hypercondensation via transmission electron microscopy, in the corpus callosum. These astrocytes exhibited markedly elevated cellular stress hallmarks, including mitochondria alteration, Golgi cisternal vesiculation/fragmentation, and endoplasmic reticulum dilation. Chronic hypoperfusion enhanced phagocytic activity and increased the lysosomal pathway in dark astrocytes. The conditional knockout of astrocytic <i>Caveolin-1</i> (<i>Cav-1</i>) prompted adaptive cellular remodeling, characterized by condensed nucleoplasm and increased organelle abundance without structural alterations. Following BCAS, astrocyte-specific <i>Cav-1</i> ablation significantly attenuated ultrastructural indicators of ischemia-related cellular stress, indicating enhanced astrocytic tolerance to chronic hypoperfusion. Most importantly, astrocytic Cav-1 deficiency ameliorated demyelination in the corpus callosum. Overall, our study provides the quantitative ultrastructural analysis of astrocytes in ischemic white matter and identifies astrocytic Cav-1 as a regulatory checkpoint for chronic ischemic demyelination.</p>

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Caveolin-1 Regulates Ultrastructural Alterations of Astrocytes in Chronic Cerebral Hypoperfusion

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年12月29日

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  • Min Wu,
  • Xiaohao Zhang,
  • Di Wang,
  • Xiuli Shu,
  • Dongyue Chen,
  • Ying Zhao,
  • Qiushi Lv,
  • Yunzi Li,
  • Zhenqian Huang,
  • Jie Gao,
  • Wusheng Zhu,
  • Zibin Wang,
  • Xinfeng Liu,
  • Yi Xie

摘要

Cerebral white matter exhibits heightened susceptibility to chronic hypoperfusion. Increasing evidence implicates glial cells, notably astrocytes, in mediating chronic ischemic demyelination. To elucidate the involvement of astrocytes in ischemic white matter pathologies, we conducted an ultrastructural characterization of intracellular contents in reactive astrocytes of mice following bilateral carotid artery stenosis (BCAS), a model of chronic cerebral hypoperfusion. BCAS triggered robust activation of astrocytes, with electron-dense dark astrocytes demonstrating cytoplasmic/nuclear hypercondensation via transmission electron microscopy, in the corpus callosum. These astrocytes exhibited markedly elevated cellular stress hallmarks, including mitochondria alteration, Golgi cisternal vesiculation/fragmentation, and endoplasmic reticulum dilation. Chronic hypoperfusion enhanced phagocytic activity and increased the lysosomal pathway in dark astrocytes. The conditional knockout of astrocytic Caveolin-1 (Cav-1) prompted adaptive cellular remodeling, characterized by condensed nucleoplasm and increased organelle abundance without structural alterations. Following BCAS, astrocyte-specific Cav-1 ablation significantly attenuated ultrastructural indicators of ischemia-related cellular stress, indicating enhanced astrocytic tolerance to chronic hypoperfusion. Most importantly, astrocytic Cav-1 deficiency ameliorated demyelination in the corpus callosum. Overall, our study provides the quantitative ultrastructural analysis of astrocytes in ischemic white matter and identifies astrocytic Cav-1 as a regulatory checkpoint for chronic ischemic demyelination.