Nanoparticle-Aided Characterization of Arterial Endothelial Architecture during Atherosclerosis Progression and Metabolic Therapy
Nanoparticle-Aided Characterization of Arterial Endothelial Architecture during Atherosclerosis Progression and Metabolic Therapy
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DOI：
10.1021/acsnano.8b08875
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发表时间：
2019-12-01
期刊：
影响因子：
17.1
通讯作者：
Kluza, Ewelina
中科院分区：
文献类型：
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作者：
Beldman, Thijs J.;Malinova, Tsveta S.;Kluza, Ewelina
动脉粥样硬化与内皮屏障受损相关，促进免疫细胞和大分子在动脉粥样硬化病变中的积聚。在这项研究中，我们研究了内皮屏障的完整性和增强的渗透性和保留（EPR）的影响，在动脉粥样硬化的进展和治疗Apoe（-/-）小鼠使用透明质酸纳米粒子（HA-NPs）。利用超微结构和正面斑块成像，我们发现了一个显着减少连接连续性动脉粥样硬化斑块覆盖内皮细胞相比，正常血管壁，表明破坏内皮屏障。有趣的是，斑块进展对连接稳定性具有积极作用，这与晚期斑块中体内施用的HA-NP的积累比早期对应物低3倍相关。此外，通过使用超分辨率和相关的光学和电子显微镜，我们跟踪斑块微环境中的纳米颗粒。我们发现纳米颗粒富集的内皮连接，含有75%的检测到的HA-NP，和高的HA-NP积累在内皮底层的细胞外基质，这表明内皮连接交通的HA-NP的鼠疫。最后，我们探讨了EPR效应HA-NPs的背景下，代谢治疗的糖酵解抑制剂，3 PO，提出了血管正常化的策略。在3 PO处理的小鼠的动脉中观察到的减弱的HA-NP摄取的趋势与在体外证明的3 PO的内皮沉默活性一致。有趣的是，该疗法还减少了斑块炎症负荷，同时激活了巨噬细胞代谢。我们的研究结果揭示了纳米颗粒在动脉粥样硬化斑块中积聚的自然限制，并提供了纳米颗粒在动脉粥样硬化内皮细胞中运输的机制。此外，我们的数据有助于动脉粥样硬化中内皮屏障调节的上升领域。
Atherosclerosis is associated with a compromised endothelial barrier, facilitating the accumulation of immune cells and macromolecules in atherosclerotic lesions. In this study, we investigate endothelial barrier integrity and the enhanced permeability and retention (EPR) effect during atherosclerosis progression and therapy in Apoe(-/-) mice using hyaluronan nanoparticles (HA-NPs). Utilizing ultrastructural and en face plaque imaging, we uncover a significantly decreased junction continuity in the atherosclerotic plaque-covering endothelium compared to the normal vessel wall, indicative of disrupted endothelial barrier. Intriguingly, the plaque advancement had a positive effect on junction stabilization, which correlated with a 3-fold lower accumulation of in vivo administrated HA-NPs in advanced plaques compared to early counterparts. Furthermore, by using super-resolution and correlative light and electron microscopy, we trace nanoparticles in the plaque microenvironment. We find nanoparticle-enriched endothelial junctions, containing 75% of detected HA-NPs, and a high HA-NP accumulation in the endothelium-underlying extracellular matrix, which suggest an endothelial junctional traffic of HA-NPs to the plague. Finally, we probe the EPR effect by HA-NPs in the context of metabolic therapy with a glycolysis inhibitor, 3PO, proposed as a vascular normalizing strategy. The observed trend of attenuated HA-NP uptake in aortas of 3PO-treated mice coincides with the endothelial silencing activity of 3PO, demonstrated in vitro. Interestingly, the therapy also reduced the plaque inflammatory burden, while activating macrophage metabolism. Our findings shed light on natural limitations of nanoparticle accumulation in atherosclerotic plaques and provide mechanistic insight into nanoparticle trafficking across the atherosclerotic endothelium. Furthermore, our data contribute to the rising field of endothelial barrier modulation in atherosclerosis.