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

Thijs J. Beldman, Tsveta S. Malinova, Emilie Desclos, Anita E. Grootemaat, Aresh L.S. Misiak, Saskia Van Der Velden, Cindy P.A.A. Van Roomen, Linda Beckers, Henk A. Van Veen, Przemyslaw M. Krawczyk, Ron A. Hoebe, Judith C. Sluimer, Annette E. Neele, Menno P.J. De Winther, Nicole N. Van Der Wel, Esther Lutgens, Willem J.M. Mulder, Stephan Huveneers, Ewelina Kluza

Research output: Contribution to journalArticlepeer-review


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.

Original languageEnglish (US)
Pages (from-to)13759-13774
Number of pages16
JournalACS Nano
Issue number12
StatePublished - Dec 24 2019


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

ASJC Scopus subject areas

  • Materials Science(all)
  • Engineering(all)
  • Physics and Astronomy(all)


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