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ACS Nano. 2019 Jul 10. doi: 10.1021/acsnano.8b08875. [Epub ahead of print]

Nanoparticle-Aided Characterization of Arterial Endothelial Architecture during Atherosclerosis Progression and Metabolic Therapy.

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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.
Cellular Imaging-Core Facility , Academic Medical Center , Amsterdam 1105 AZ , The Netherlands.
Department of Medical Biology , Amsterdam University Medical Center , Amsterdam 1105 AZ , The Netherlands.
Department of Pathology, Cardiovascular Research Institute Maastricht (CARIM) , Maastricht University Medical Center , Maastricht 6229 ER , The Netherlands.
Institute for Cardiovascular Prevention , Ludwig Maximilians University , Munich 80336 , Germany.
Translational and Molecular Imaging Institute , Icahn School of Medicine at Mount Sinai , New York , New York 10029 , United States.


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.


atherosclerosis; endothelial normalization; enhanced permeability and retention effect; nanomedicine; vascular endothelial cadherin


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