Abstract
BackgroundαVβ3-integrin is expressed by activated endothelial cells and macrophages in atherosclerotic plaques and may represent a valuable marker of high-risk plaques. We evaluated 99mTc-maraciclatide, an integrin-specific tracer, for imaging vascular inflammation in atherosclerotic lesions in mice.MethodsApolipoprotein E-negative (ApoE−/−) mice on a Western diet (n = 10) and normally fed adult C57BL/6 control mice (n = 4) were injected with 99mTc-maraciclatide (51.8 ± 3.7 MBq). A blocking peptide was infused in three ApoE−/− mice; this condition served as another control. After 90 min, the animals were imaged via single-photon emission computed tomography (SPECT). While maintained in the same position, the mice were transferred to computed tomography (CT) to obtain contrast-enhanced images of the aortic arch. Images from both modalities were fused, and signal was quantified in the aortic arch and in the vena cava for subtraction of blood-pool activity. The aorta was carefully dissected after imaging for gamma counting, autoradiography, and histology.ResultsTracer uptake was significantly higher in ApoE−/− mice than in both groups of control mice (1.56 ± 0.33 vs. 0.82 ± 0.24 vs. 0.98 ± 0.11, respectively; P = 0.006). Furthermore, higher tracer activity was detected via gamma counting in the aorta of hypercholesterolemic mice than in both groups of control mice (1.52 ± 0.43 vs. 0.78 ± 0.19 vs. 0.47 ± 0.31 99mTc-maraciclatide %ID/g, respectively; P = 0.018). Autoradiography showed significantly higher tracer uptake in the atherosclerotic aorta than in the control aorta (P = 0.026). Finally, in the atherosclerotic aorta, immunostaining indicated that the integrin signal came predominantly from macrophages and was correlated with the macrophage CD68 immunomarker (r = 0.73).Conclusions99mTc-maraciclatide allows in vivo detection of inflamed atherosclerotic plaques in mice and may represent a non-invasive approach for identifying high-risk plaques in patients.
Highlights
ΑVβ3-integrin is expressed by activated endothelial cells and macrophages in atherosclerotic plaques and may represent a valuable marker of high-risk plaques
All apolipoprotein E (ApoE)−/− mice had atherosclerotic plaques predominantly located at the level of the aortic arch and the supra-aortic vessels (Fig. 2a)
Increased tracer uptake was readily visible on the aortic arch of ApoE−/− mice that did not receive the blocking peptide (Fig. 3a)
Summary
ΑVβ3-integrin is expressed by activated endothelial cells and macrophages in atherosclerotic plaques and may represent a valuable marker of high-risk plaques. We evaluated 99mTc-maraciclatide, an integrin-specific tracer, for imaging vascular inflammation in atherosclerotic lesions in mice. Higher tracer activity was detected via gamma counting in the aorta of hypercholesterolemic mice than in both groups of control mice (1.52 ± 0.43 vs 0.78 ± 0.19 vs 0.47 ± 0.31 99mTc-maraciclatide %ID/g, respectively; P = 0.018). The αVβ3 integrin is a ubiquitous receptor that is expressed on a variety of cell types; it interacts with ligands present in the extracellular matrix or expressed on the cell surface This integrin plays a role in diverse biological processes. ΑVβ3 integrin is detected in situ on Vancraeynest et al EJNMMI Research (2016) 6:29 macrophages in early and advanced atherosclerotic lesions and could regulate macrophage functional maturation into foam cells [5]. Several tracers for positron emission tomography (PET) and magnetic resonance imaging (MRI) that display highly specific binding to the αVβ3 integrin have been successfully tested in animal models of vascular inflammation [7,8,9] and in human carotid atherosclerosis [10]
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