Abstract
Atherosclerosis is a lipid-driven chronic inflammatory disease that leads to the formation of plaques in the inner lining of arteries. Plaques form over a range of phenotypes, the most severe of which is vulnerable to rupture and causes most of the clinically significant events. In this study, we evaluated the efficacy of nanoparticles (NPs) to differentiate between two plaque phenotypes based on accumulation kinetics in a mouse model of atherosclerosis. This model uses a perivascular cuff to induce two regions of disturbed wall shear stress (WSS) on the inner lining of the instrumented artery, low (upstream) and multidirectional (downstream), which, in turn, cause the development of an unstable and stable plaque phenotype, respectively. To evaluate the influence of each WSS condition, in addition to the final plaque phenotype, in determining NP uptake, mice were injected with NPs at intermediate and fully developed stages of plaque growth. The kinetics of artery wall uptake were assessed in vivo using dynamic contrast-enhanced magnetic resonance imaging. At the intermediate stage, there was no difference in NP uptake between the two WSS conditions, although both were different from the control arteries. At the fully-developed stage, however, NP uptake was reduced in plaques induced by low WSS, but not multidirectional WSS. Histological evaluation of plaques induced by low WSS revealed a significant inverse correlation between the presence of smooth muscle cells and NP accumulation, particularly at the plaque-lumen interface, which did not exist with other constituents (lipid and collagen) and was not present in plaques induced by multidirectional WSS. These findings demonstrate that NP accumulation can be used to differentiate between unstable and stable murine atherosclerosis, but accumulation kinetics are not directly influenced by the WSS condition. This tool could be used as a diagnostic to evaluate the efficacy of experimental therapeutics for atherosclerosis.
Highlights
Atherosclerosis is a chronic inflammatory disease characterized by the development of plaques composed of lipids and immune cells within the artery wall
Histological evaluation of plaques induced by low wall shear stress (WSS) revealed a significant inverse correlation between the presence of smooth muscle cells and NP accumulation, at the plaque-lumen interface, which did not exist with other constituents and was not present in plaques induced by multidirectional WSS
We found that the plaque constituent exhibiting the most significant correlation with Ktrans was α-SMA at the plaque-lumen interface of plaques induced by low WSS
Summary
Atherosclerosis is a chronic inflammatory disease characterized by the development of plaques composed of lipids and immune cells within the artery wall. While other imaging modalities can be used to better quantify additional features of plaque phenotype (e.g., intravascular ultrasound), all of them require invasive catheterization that carries risk of major complications to the patient [3]. Another problem with diagnosis of high-risk plaques is that progression to rupture is a highly nonlinear process, where plaque features can change rapidly in the weeks to months before rupture [4, 5]. Given the dynamic nature of plaque evolution, such a tool could be impactful in research that employs animal models to characterize plaque progression and regression To address this need, contrast-enhancing nanoparticles (NPs) can be tracked in atherosclerotic arteries to relate accumulation in plaques to plaque phenotype and changes with progression. While studies have examined NP accumulation in atherosclerosis [6], in general, few have looked at changes with plaque progression and the large range of NP properties alone, including size, targeting ligands, and surface coating, warrant additional studies
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