Fluid shear stress induced-endothelial phenotypic transition contributes to cerebral ischemia-reperfusion injury and repair.

IF 6.6 3区 医学 Q1 ENGINEERING, BIOMEDICAL
APL Bioengineering Pub Date : 2024-02-26 eCollection Date: 2024-03-01 DOI:10.1063/5.0174825
Denglian Sun, Jia Ma, Lingyu Du, Qiao Liu, Hongyan Yue, Chengxiu Peng, Hanxiao Chen, Guixue Wang, Xiaoheng Liu, Yang Shen
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Abstract

Long-term ischemia leads to insufficient cerebral microvascular perfusion and dysfunction. Reperfusion restores physiological fluid shear stress (FSS) but leads to serious injury. The mechanism underlying FSS-induced endothelial injury in ischemia-reperfusion injury (IRI) remains poorly understood. In this study, a rat model of middle cerebral artery occlusion was constructed to explore cerebrovascular endothelial function and inflammation in vivo. Additionally, the rat brain microvascular endothelial cells (rBMECs) were exposed to a laminar FSS of 0.5 dyn/cm2 for 6 h and subsequently restored to physiological fluid shear stress level (2 dyn/cm2) for 2 and 12 h, respectively. We found that reperfusion induced endothelial-to-mesenchymal transition (EndMT) in endothelial cells, leading to serious blood-brain barrier dysfunction and endothelial inflammation, accompanied by the nuclear accumulation of Yes-associated protein (YAP). During the later stage of reperfusion, cerebral endothelium was restored to the endothelial phenotype with a distinct change in mesenchymal-to-endothelial transition (MEndT), while YAP was translocated and phosphorylated in the cytoplasm. Knockdown of YAP or inhibition of actin polymerization markedly impaired the EndMT in rBMECs. These findings suggest that ischemia-reperfusion increased intensity of FSS triggered an EndMT process and, thus, led to endothelial inflammation and tissue injury, whereas continuous FSS induced a time-dependent reversal MEndT event contributing to the endothelial repair. This study provides valuable insight for therapeutic strategies targeting IRI.

流体剪切应力诱导的内皮表型转变有助于脑缺血再灌注损伤和修复。
长期缺血会导致脑微血管灌注不足和功能障碍。再灌注可恢复生理性流体剪切应力(FSS),但会导致严重损伤。缺血再灌注损伤(IRI)中 FSS 诱导内皮损伤的机制仍不甚明了。本研究构建了大鼠大脑中动脉闭塞模型,以探讨体内脑血管内皮功能和炎症。此外,将大鼠脑微血管内皮细胞(rBMECs)暴露在 0.5 dyn/cm2 的层流流体剪切应力下 6 小时,然后分别恢复到生理流体剪切应力水平(2 dyn/cm2)2 小时和 12 小时。我们发现,再灌注诱导了内皮细胞的内皮向间质转化(EndMT),导致严重的血脑屏障功能障碍和内皮炎症,并伴有Yes相关蛋白(YAP)的核聚集。在再灌注后期,脑内皮恢复到内皮表型,间充质向内皮转化(MEndT)发生明显变化,而YAP则在细胞质中转位和磷酸化。敲除 YAP 或抑制肌动蛋白聚合可明显减弱 rBMECs 的 EndMT。这些研究结果表明,缺血再灌注增加的 FSS 强度会触发 EndMT 过程,从而导致内皮炎症和组织损伤,而持续的 FSS 会诱导 MEndT 事件的时间依赖性逆转,从而促进内皮修复。这项研究为针对 IRI 的治疗策略提供了宝贵的见解。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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来源期刊
APL Bioengineering
APL Bioengineering ENGINEERING, BIOMEDICAL-
CiteScore
9.30
自引率
6.70%
发文量
39
审稿时长
19 weeks
期刊介绍: APL Bioengineering is devoted to research at the intersection of biology, physics, and engineering. The journal publishes high-impact manuscripts specific to the understanding and advancement of physics and engineering of biological systems. APL Bioengineering is the new home for the bioengineering and biomedical research communities. APL Bioengineering publishes original research articles, reviews, and perspectives. Topical coverage includes: -Biofabrication and Bioprinting -Biomedical Materials, Sensors, and Imaging -Engineered Living Systems -Cell and Tissue Engineering -Regenerative Medicine -Molecular, Cell, and Tissue Biomechanics -Systems Biology and Computational Biology
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