Endothelial β-Catenin Deficiency Causes Blood-Brain Barrier Breakdown via Enhancing the Paracellular and Transcellular Permeability.
Endothelial β-Catenin Deficiency Causes Blood-Brain Barrier Breakdown via Enhancing the Paracellular and Transcellular Permeability.
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内皮β-连环蛋白缺乏通过增强细胞旁和跨细胞渗透性导致血脑屏障破坏
DOI：
10.3389/fnmol.2022.895429
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发表时间：
2022
影响因子：
4.8
通讯作者：
Chang, Junlei
中科院分区：
文献类型：
--
作者：
Hussain, Basharat;Fang, Cheng;Huang, Xiaowen;Feng, Ziying;Yao, Yuxuan;Wang, Yu;Chang, Junlei
血脑屏障(BBB)的破坏导致或促成了神经元功能障碍和几种中枢神经系统(CNS)疾病。Wnt/β-Catenin信号转导通路对于维持成人血脑屏障在生理和病理条件下(包括中风)的完整性是必不可少的。然而，内皮细胞Wnt/β-catenin信号的损伤如何导致血脑屏障的破坏仍不清楚。此外，不同的血脑屏障通透性诱导机制，包括细胞间连接损伤、内皮细胞穿透和开窗，其个体作用尚不清楚。在这里，我们在成年小鼠中诱导了β-连环蛋白内皮特异性条件性基因敲除(ECKO)，并确定了其对血脑屏障通透性的影响及其潜在机制。β-catenin ECKO降低了小鼠体内活性β-catenin的水平和Wnt靶基因的mR-NA水平，提示内皮细胞Wnt/β-catenin信号的下调。β-catenin ECKO小鼠表现出严重而广泛的血浆免疫球蛋白和白蛋白渗入大脑皮层，这在野生型对照组中是不存在的。从机制上讲，β-catenin ECKO小鼠的细胞旁和跨细胞转运途径都受到了破坏。首先，β-catenin ECKO降低了脑内皮细胞紧密连接蛋白水平，并破坏了细胞间连接超微结构。其次，β-catenin ECKO通过下调Mfsd2a和上调Caveolin-1的表达，显著增加了内皮囊泡和小凹介导的细胞转运。有趣的是，在β-catenin ECKO小鼠中没有观察到窗口标记Plvap的开窗和上调表达。总体而言，我们的研究表明，内皮Wnt/β-catenin信号通过调节细胞旁和跨细胞的通透性来维持成人血脑屏障的完整性。这些发现可能在了解和治疗涉及血脑屏障中断的中枢神经系统疾病方面有广泛的应用。
Disruption of the blood-brain barrier (BBB) causes or contributes to neuronal dysfunction and several central nervous system (CNS) disorders. Wnt/β-catenin signaling is essential for maintaining the integrity of the adult BBB in physiological and pathological conditions, including stroke. However, how the impairment of the endothelial Wnt/β-catenin signaling results in BBB breakdown remains unclear. Furthermore, the individual contributions of different BBB permeability-inducing mechanisms, including intercellular junction damage, endothelial transcytosis, and fenestration, remains unexplored. Here, we induced β-catenin endothelial-specific conditional knockout (ECKO) in adult mice and determined its impact on BBB permeability and the underlying mechanism. β-catenin ECKO reduced the levels of active β-catenin and the mRNA levels of Wnt target genes in mice, indicating downregulation of endothelial Wnt/β-catenin signaling. β-catenin ECKO mice displayed severe and widespread leakage of plasma IgG and albumin into the cerebral cortex, which was absent in wild-type controls. Mechanistically, both the paracellular and transcellular transport routes were disrupted in β-catenin ECKO mice. First, β-catenin ECKO reduced the tight junction protein levels and disrupted the intercellular junction ultrastructure in the brain endothelium. Second, β-catenin ECKO substantially increased the number of endothelial vesicles and caveolae-mediated transcytosis through downregulating Mfsd2a and upregulating caveolin-1 expression. Interestingly, fenestration and upregulated expression of the fenestration marker Plvap were not observed in β-catenin ECKO mice. Overall, our study reveals that endothelial Wnt/β-catenin signaling maintains adult BBB integrity via regulating the paracellular as well as transcellular permeability. These findings may have broad applications in understanding and treatment of CNS disorders involving BBB disruption.
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