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

doi:10.1021/acsnano.8b08875

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 (Corresponding author)

Precision Medicine

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Abstract

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 language	English
Pages (from-to)	13759-13774
Number of pages	16
Journal	ACS Nano
Volume	13
Issue number	12
DOIs	https://doi.org/10.1021/acsnano.8b08875
Publication status	Published - 24 Dec 2019

Funding

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.

Keywords

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

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10.1021/acsnano.8b08875Licence: CC BY-NC-ND

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Beldman, T. J., Malinova, T. S., Desclos, E., Grootemaat, A. E., Misiak, A. L. S., van der Velden, S., van Roomen, C. P. A. A., Beckers, L., van Veen, H. A., Krawczyk, P. M., Hoebe, R. A., Sluimer, J. C., Neele, A. E., de Winther, M. P. J., van der Wel, N. N., Lutgens, E., Mulder, W. J. M., Huveneers, S., & Kluza, E. (2019). Nanoparticle-Aided Characterization of Arterial Endothelial Architecture during Atherosclerosis Progression and Metabolic Therapy. ACS Nano, 13(12), 13759-13774. https://doi.org/10.1021/acsnano.8b08875

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title = "Nanoparticle-Aided Characterization of Arterial Endothelial Architecture during Atherosclerosis Progression and Metabolic Therapy",

abstract = "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.",

keywords = "atherosclerosis, endothelial normalization, enhanced permeability and retention effect, nanomedicine, vascular endothelial cadherin",

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

year = "2019",

month = dec,

day = "24",

doi = "10.1021/acsnano.8b08875",

language = "English",

volume = "13",

pages = "13759--13774",

journal = "ACS Nano",

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Beldman, TJ, Malinova, TS, Desclos, E, Grootemaat, AE, Misiak, ALS, van der Velden, S, van Roomen, CPAA, Beckers, L, van Veen, HA, Krawczyk, PM, Hoebe, RA, Sluimer, JC, Neele, AE, de Winther, MPJ, van der Wel, NN, Lutgens, E, Mulder, WJM, Huveneers, S & Kluza, E 2019, 'Nanoparticle-Aided Characterization of Arterial Endothelial Architecture during Atherosclerosis Progression and Metabolic Therapy', ACS Nano, vol. 13, no. 12, pp. 13759-13774. https://doi.org/10.1021/acsnano.8b08875

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

PY - 2019/12/24

Y1 - 2019/12/24

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 - atherosclerosis

KW - endothelial normalization

KW - enhanced permeability and retention effect

KW - nanomedicine

KW - vascular endothelial cadherin

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U2 - 10.1021/acsnano.8b08875

DO - 10.1021/acsnano.8b08875

M3 - Article

C2 - 31268670

AN - SCOPUS:85077225110

SN - 1936-0851

VL - 13

SP - 13759

EP - 13774

JO - ACS Nano

JF - ACS Nano

IS - 12

ER -

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

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