Glycocalyx is critical for blood-brain barrier integrity by suppressing caveolin1-dependent endothelial transcytosis following ischemic stroke.
Glycocalyx is critical for blood-brain barrier integrity by suppressing caveolin1-dependent endothelial transcytosis following ischemic stroke.
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糖萼通过抑制缺血性中风后的 Caveolin1 依赖性内皮转胞吞作用，对血脑屏障的完整性至关重要
DOI：
10.1111/bpa.13006
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发表时间：
2022-01
期刊：
影响因子：
--
通讯作者：
Pan S
中科院分区：
文献类型：
--
作者：
Zhu J;Li Z;Ji Z;Wu Y;He Y;Liu K;Chang Y;Peng Y;Lin Z;Wang S;Wang D;Huang K;Pan S
血脑屏障（BBB）的破坏与缺血性脑卒中神经功能障碍的发生和恶化有关，导致血源性物质外渗，导致血管源性水肿，死亡率增加。然而，对控制血脑屏障限制性特性的分子机制的有限理解阻碍了在疾病和治疗中对血脑屏障的操纵。在这里，我们发现，糖萼（GCX）是一个关键因素，在调节脑内皮屏障的完整性。首先，内皮GCX显示出双相变化模式，其时间尺度与t-MCAO后第一周内BBB对示踪剂渗透性的双相演变非常匹配。此外，用透明质酸酶破坏GCX增加了健康小鼠的BBB通透性，并加重了短暂性大脑中动脉闭塞（t-MCAO）小鼠的BBB渗漏。令人惊讶的是，超微结构观察表明，GCX破坏伴随着增加内皮细胞胞吞作用在缺血血脑屏障，而紧密连接保持形态和功能完整。敲低小窝蛋白1（Cav 1）抑制内皮细胞转胞吞作用，导致BBB通透性降低和脑水肿。最后，免疫共沉淀试验表明，GCX降解通过促进磷酸化syndecan 1与Src SH 2结构域的结合来增强syndecan 1和Src之间的相互作用，这导致细胞骨架蛋白的快速调节以促进小窝介导的内吞作用。总体而言，这些研究结果表明，GCX的动态降解和重建可能占缺血性卒中中BBB通透性的双相变化，并揭示了GCX在抑制脑内皮细胞跨细胞转运以维持BBB完整性方面的重要作用。靶向GCX可能为控制BBB功能障碍和中枢神经系统药物递送提供新的策略。糖萼调节的跨血脑屏障的跨细胞转运在正常和疾病条件下都对血脑屏障的屏障功能有显著贡献。GCX可能是操纵血脑屏障通透性的重要靶点，以帮助药物递送至大脑或在疾病条件下保护免受血脑屏障损伤。
The breakdown of the blood‐brain barrier (BBB) is related to the occurrence and deterioration of neurological dysfunction in ischemic stroke, which leads to the extravasation of blood‐borne substances, resulting in vasogenic edema and increased mortality. However, a limited understanding of the molecular mechanisms that control the restrictive properties of the BBB hinders the manipulation of the BBB in disease and treatment. Here, we found that the glycocalyx (GCX) is a critical factor in the regulation of brain endothelial barrier integrity. First, endothelial GCX displayed a biphasic change pattern, of which the timescale matched well with the biphasic evolution of BBB permeability to tracers within the first week after t‐MCAO. Moreover, GCX destruction with hyaluronidase increased BBB permeability in healthy mice and aggravated BBB leakage in transient middle cerebral artery occlusion (t‐MCAO) mice. Surprisingly, ultrastructural observation showed that GCX destruction was accompanied by increased endothelial transcytosis at the ischemic BBB, while the tight junctions remained morphologically and functionally intact. Knockdown of caveolin1 (Cav1) suppressed endothelial transcytosis, leading to reduced BBB permeability, and brain edema. Lastly, a coimmunoprecipitation assay showed that GCX degradation enhanced the interaction between syndecan1 and Src by promoting the binding of phosphorylated syndecan1 to the Src SH2 domain, which led to rapid modulation of cytoskeletal proteins to promote caveolae‐mediated endocytosis. Overall, these findings demonstrate that the dynamic degradation and reconstruction of GCX may account for the biphasic changes in BBB permeability in ischemic stroke, and reveal an essential role of GCX in suppressing transcellular transport in brain endothelial cells to maintain BBB integrity. Targeting GCX may provide a novel strategy for managing BBB dysfunction and central nervous system drug delivery. Glycocalyx‐regulated transcellular transport across the BBB contributes significantly to the barrier function of the BBB in both normal and diseased conditions. GCX may be an essential target for manipulating BBB permeability to help with drug delivery to the brain or to protect against BBB injury under diseased conditions.
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影响因子：
3.1
作者：
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