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

作者：Na Xu, Xiaoyan Jiang, Wenting Zhang, Yejie Shi, Rehana K. Leak, Richard F. Keep, Qing Ye, Tuo Yang, Sicheng Li, Xiaoming Hu, R. Anne Stetler, Michael V. L. Bennett, Jun Chen · 发表于：Proceedings of the National Academy of Sciences · 年份：2024 · DOI：10.1073/pnas.2400272121 · 被引用次数：24 · 研究领域：Redox biology and oxidative stress、S100 Proteins and Annexins、Connexins and lens biology

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...