Experimental Vascular Biology, Department of Medical Biochemistry, Amsterdam Cardiovascular Sciences (ACS) , Amsterdam University Medical Center , Amsterdam 1105 AZ , The Netherlands.
Vascular Microenvironment and Integrity, Department of Medical Biochemistry, Amsterdam Cardiovascular Sciences (ACS) , Amsterdam University Medical Center , Amsterdam 1105 AZ , The Netherlands.
ACS Nano. 2019 Dec 24;13(12):13759-13774. doi: 10.1021/acsnano.8b08875. Epub 2019 Jul 10.
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 mice using hyaluronan nanoparticles (HA-NPs). Utilizing ultrastructural and 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 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 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.
动脉粥样硬化与内皮屏障受损有关，这促进了免疫细胞和大分子在动脉粥样硬化病变中的积累。在这项研究中，我们使用透明质酸纳米颗粒（HA-NPs）在小鼠中研究动脉粥样硬化进展和治疗过程中的内皮屏障完整性和增强的通透性和保留（EPR）效应。通过超微结构和斑块成像，我们发现与正常血管壁相比，斑块覆盖的内皮中的连接连续性明显降低，表明内皮屏障受损。有趣的是，斑块进展对连接的稳定性有积极影响，这与晚期斑块中 HA-NPs 的积累量比早期斑块低 3 倍相关。此外，通过使用超分辨率和相关的光和电子显微镜，我们追踪斑块微环境中的纳米颗粒。我们发现富含纳米颗粒的内皮连接，其中包含 75%检测到的 HA-NPs，并且在血管内皮细胞下的细胞外基质中 HA-NP 大量积累，这表明 HA-NPs 通过内皮连接向斑块的运输。最后，我们在代谢治疗的背景下用糖酵解抑制剂 3PO 研究了 HA-NPs 的 EPR 效应，3PO 被提议作为一种血管正常化策略。观察到的 3PO 处理小鼠主动脉中 HA-NP 摄取减少的趋势与 3PO 的内皮沉默活性一致，有趣的是，该治疗还减少了斑块的炎症负担，同时激活了巨噬细胞代谢。我们的发现揭示了纳米颗粒在动脉粥样硬化斑块中积累的自然局限性，并为纳米颗粒穿过动脉粥样硬化内皮的运输提供了机制见解。此外，我们的数据为动脉粥样硬化中内皮屏障调节这一日益兴起的领域做出了贡献。
