TY - JOUR
T1 - Nanoparticle-Aided Characterization of Arterial Endothelial Architecture during Atherosclerosis Progression and Metabolic Therapy
AU - Beldman, Thijs J.
AU - Malinova, Tsveta S.
AU - Desclos, Emilie
AU - Grootemaat, Anita E.
AU - Misiak, Aresh L. S.
AU - van der Velden, Saskia
AU - van Roomen, Cindy P. A. A.
AU - Beckers, Linda
AU - van Veen, Henk A.
AU - Krawczyk, Przemyslaw M.
AU - Hoebe, Ron A.
AU - Sluimer, Judith C.
AU - Neele, Annette E.
AU - de Winther, Menno P. J.
AU - van der Wel, Nicole N.
AU - Lutgens, Esther
AU - Mulder, Willem J. M.
AU - Huveneers, Stephan
AU - Kluza, Ewelina
N1 - Funding Information:
This work was financially supported by National Institutes of Health grants R01 HL118440 (W.J.M.M.), R01 HL125703 (W.J.M.M.), R01 CA155432 (W.J.M.M.), as well as The Netherlands Organization for Scientific Research (NWO) Vidi (016.136.324, W.J.M.M.), Vidi (016.156.327, S.H.), STW (15851, W.J.M.M.), and Vici (016.176.622, W.J.M.M.). The authors also thank Sensi Pharma BV for their funding. We thank Ralph J. Sinn and Pascal J. H. Kusters for help with histopathological preparation and analysis.
Publisher Copyright:
© 2019 American Chemical Society.
PY - 2019/12
Y1 - 2019/12
N2 - 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.
AB - 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.
KW - nanomedicine
KW - atherosclerosis
KW - enhanced permeability and retention effect
KW - endothelial normalization
KW - vascular endothelial cadherin
KW - APOLIPOPROTEIN-E
KW - VE-CADHERIN
KW - INTIMAL NEOVASCULARIZATION
KW - ENHANCED PERMEABILITY
KW - VASA VASORUM
KW - FDG-PET
KW - PLAQUE
KW - MACROPHAGES
KW - JUNCTIONS
KW - CELL
U2 - 10.1021/acsnano.8b08875
DO - 10.1021/acsnano.8b08875
M3 - Article
C2 - 31268670
SN - 1936-0851
VL - 13
SP - 13759
EP - 13774
JO - ACS Nano
JF - ACS Nano
IS - 12
ER -