Endothelial peroxiredoxin-4 is indispensable for blood-brain barrier integrity and long- term functional recovery after ischemic stroke

• 成果类型: Article
• 署名作者: Xu, Na; Jiang, Xiaoyan; Zhang, Wenting; Shi, Yejie; Leak, Rehana K.; Keep, Richard F.; Ye, Qing; Yang, Tuo; Li, Sicheng; Hu, Xiaoming; Stetler, R. Anne; Bennett, Michael V. L.; Chen, Jun
• 署名单位: Pennsylvania Commonwealth System of Higher Education (PCSHE); University of Pittsburgh; Pennsylvania Commonwealth System of Higher Education (PCSHE); University of Pittsburgh; US Department of Veterans Affairs; Veterans Health Administration (VHA); VA Pittsburgh Healthcare System; Geriatric Research Education & Clinical Center; Duquesne University; University of Michigan System; University of Michigan; Yeshiva University; Montefiore Medical Center; Albert Einstein College of Medicine
• 刊物名称: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
• ISSN/ISSBN: 0027-10714
• DOI: 10.1073/pnas.2400272121
• 发表日期: 2024-03-12
• 关键词: breakdown

摘要

The endothelial lining of cerebral microvessels is damaged relatively early after cerebral ischemia/reperfusion (I/R) injury and mediates blood-brain barrier (BBB) disruption, neurovascular injury, and long - term neurological deficits. I/R induces BBB leakage within 1 h due to subtle structural alterations in endothelial cells (ECs), including reorganization of the actin cytoskeleton and subcellular redistribution of junctional proteins. Herein, we show that the protein peroxiredoxin-4 (Prx4) is an endogenous protectant against endothelial dysfunction and BBB damage in a murine I/R model. We observed a transient upregulation of Prx4 in brain ECs 6 h after I/R in wild - type (WT) mice, whereas tamoxifen- induced, selective knockout of Prx4 from endothelial cells (eKO) mice dramatically raised vulnerability to I/R. Specifically, eKO mice displayed more BBB damage than WT mice within 1 to 24 h after I/R and worse long - term neurological deficits and focal brain atrophy by 35 d. Conversely, endothelium- targeted transgenic (eTG) mice overexpressing Prx4 were resistant to I/R- induced early BBB damage and had better long - term functional outcomes. As demonstrated in cultures of human brain endothelial cells and in animal models of I/R, Prx4 suppresses actin polymerization and stress fiber formation in brain ECs, at least in part by inhibiting phosphorylation/ activation of myosin light chain. The latter cascade prevents redistribution of junctional proteins and BBB leakage under conditions of Prx4 repletion. Prx4 also tempers microvascular inflammation and infiltration of destructive neutrophils and proinflammatory macrophages into the brain parenchyma after I/R. Thus, the evidence supports an indispensable role for endothelial Prx4 in safeguarding the BBB and promoting functional recovery after I/R brain injury.