Targeting endothelial tight junctions to predict and protect thoracic aortic aneurysm and dissection
Targeting endothelial tight junctions to predict and protect thoracic aortic aneurysm and dissection
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DOI：
10.1093/eurheartj/ehac823
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发表时间：
2023-01-14
影响因子：
39.3
通讯作者：
Kong, Wei
中科院分区：
文献类型：
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作者：
Yang, Xueyuan;Xu, Chen;Kong, Wei
内皮紧密连接（TJ）的改变是否导致胸主动脉瘤和夹层（TAAD）的形成，并作为早期指标和治疗靶点仍然是一个谜。方法和结果单细胞RNA测序分析显示TAAD患者胸主动脉瘤中内皮TJ表达异常。在β-氨基丙腈（BAPN）诱导的TAAD小鼠模型中，通过血管通透性测定观察到，在早期阶段（5天和10天），胸主动脉中的内皮TJ功能被破坏，而通过正面染色观察到关键TJ组分的细胞间分布显著减少。对于内皮TJ功能的非侵入性检测，将分子量为4和70 kDa的两种葡聚糖与磁共振成像（MRI）造影剂Gd-DOTA缀合以合成FITC-葡聚糖-DOTA-Gd和罗丹明B-葡聚糖-DOTA-Gd。MRI图像显示，这两种探针在BAPN喂养的小鼠的胸部肿块中积累。特别是，从5天到10天累积信号增加的小鼠在14天出现TAAD，而在两个时间点之间具有相似信号的小鼠则没有。此外，蛋白酶激活受体2抑制剂AT-1001，密封TJ，减轻BAPN诱导的内皮TJ功能和表达的损害，随后降低TAAD的发病率。值得注意的是，内皮靶向ZO-1条件性敲除增加了TAAD的发生率。从机制上讲，在BAPN喂养的小鼠的胸主动脉中观察到血管炎症和水肿，而这些现象被AT-1001减弱。结论内皮TJ功能的破坏是TAAD形成前的早期事件，是TAAD的潜在指标和有希望的靶点。
Aims Whether changes in endothelial tight junctions (TJs) lead to the formation of thoracic aortic aneurysm and dissection (TAAD) and serve as an early indicator and therapeutic target remains elusive. Methods and results Single-cell RNA sequencing analysis showed aberrant endothelial TJ expressions in the thoracic aortas of patients with TAAD. In a beta-aminopropionitrile (BAPN)-induced TAAD mouse model, endothelial TJ function was disrupted in the thoracic aortas at an early stage (5 and 10 days) as observed by a vascular permeability assay, while the intercellular distribution of crucial TJ components was significantly decreased by en face staining. For the non-invasive detection of endothelial TJ function, two dextrans of molecular weights 4 and 70 kDa were conjugated with the magnetic resonance imaging (MRI) contrast agent Gd-DOTA to synthesize FITC-dextran-DOTA-Gd and rhodamine B-dextran-DOTA-Gd. MRI images showed that both probes accumulated in the thoracic aortas of the BAPN-fed mice. Particularly, the mice with increased accumulated signals from 5 to 10 days developed TAAD at 14 days, whereas the mice with similar signals between the two time points did not. Furthermore, the protease-activated receptor 2 inhibitor AT-1001, which seals TJs, alleviated the BAPN-induced impairment of endothelial TJ function and expression and subsequently reduced TAAD incidence. Notably, endothelial-targeted ZO-1 conditional knockout increased TAAD incidence. Mechanistically, vascular inflammation and edema were observed in the thoracic aortas of the BAPN-fed mice, whereas these phenomena were attenuated by AT-1001. Conclusion The disruption of endothelial TJ function is an early event prior to TAAD formation, herein serving as a potential indicator and a promising target for TAAD.