Uptake of citrate-coated iron oxide nanoparticles into atherosclerotic lesions in mice occurs via accelerated transcytosis through plaque endothelial cells
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Verena Stangl1,6(
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An erratum to this article is available online at https://doi.org/10.1007/s12274-016-1337-x
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Very small superparamagnetic iron oxide nanoparticles (VSOPs) rapidly accumulate in atherosclerotic lesions, thereby enabling plaque visualization by magnetic resonance imaging (MRI). This study was performed to identify the uptake mechanisms of VSOPs into atherosclerotic plaques. Low-density lipoprotein receptor-deficient (LDLR-/-) mice with advanced atherosclerosis were analyzed using MRI and transmission electron microscopy (TEM) at various time points after intravenous administration of VSOPs. Post-mortem MRI detected VSOP labeling of atherosclerotic plaques 10 min after injection, and the signal increased over the first 3 h. TEM revealed that the intensive plaque labeling was mediated by accelerated transcytosis of VSOPs through endothelial cells overlaying atherosclerotic lesions. Experiments with endocytosis inhibitors and small interfering RNA (siRNA) revealed a dynamin-dependent mechanism involving both clathrin- and caveolin-mediated processes. In cell culture experiments, endothelial VSOP uptake was enhanced under proatherogenic flow and TNFα stimulation, conditions that are both present in plaque areas. Our study demonstrates that VSOPs enable non-invasive MRI assessment of accelerated endothelial transcytosis, an important pathomechanism in atherosclerotic plaque formation.
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Uptake of citrate-coated iron oxide nanoparticles into atherosclerotic lesions in mice occurs via accelerated transcytosis through plaque endothelial cells
), Verena Stangl1,6(
),
Abstract
Very small superparamagnetic iron oxide nanoparticles (VSOPs) rapidly accumulate in atherosclerotic lesions, thereby enabling plaque visualization by magnetic resonance imaging (MRI). This study was performed to identify the uptake mechanisms of VSOPs into atherosclerotic plaques. Low-density lipoprotein receptor-deficient (LDLR-/-) mice with advanced atherosclerosis were analyzed using MRI and transmission electron microscopy (TEM) at various time points after intravenous administration of VSOPs. Post-mortem MRI detected VSOP labeling of atherosclerotic plaques 10 min after injection, and the signal increased over the first 3 h. TEM revealed that the intensive plaque labeling was mediated by accelerated transcytosis of VSOPs through endothelial cells overlaying atherosclerotic lesions. Experiments with endocytosis inhibitors and small interfering RNA (siRNA) revealed a dynamin-dependent mechanism involving both clathrin- and caveolin-mediated processes. In cell culture experiments, endothelial VSOP uptake was enhanced under proatherogenic flow and TNFα stimulation, conditions that are both present in plaque areas. Our study demonstrates that VSOPs enable non-invasive MRI assessment of accelerated endothelial transcytosis, an important pathomechanism in atherosclerotic plaque formation.
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Acknowledgements
The project was supported by the Deutsche Forschungsgemeinschaft (DFG) within the Clinical Research Unit KFO 213 (Nos. STA 481/1-2, LU 1559/1-2, TA 166/7-2, and WA 3105/1-2) and the Bundesministerium für Bildung und Forschung (BMBF) (No. DZHK B15-028). Additional funding was provided by the DFG (EXC Neurocure) and the BMBF (01EO0801, Center for Stroke Research Berlin) and 01EW1201 under the ERA-NET-NEURON scheme funded by the European Commission (PBS). We highly appreciate the excellent technical assistance of A. Stach, S. Metzkow, and M. Andratzek. ES provided the molecular model of VSOP in the graphical abstract. WCP is participant in the BIH-Charité Clinical Scientist Program funded by the Charité-Universitätsmedizin Berlin and the Berlin Institute of Health.
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