Molecular imaging of endothelial activation and mineralization in a mouse model of accelerated atherosclerosis

Abstract

Purpose Preclinical imaging of endothelial activation and mineralization using both positron emission tomography (PET) and magnetic resonance (MR) remains scarce. Procedures A group of uremic ApoE −/− (Ur), non-uremic ApoE −/− (NUr), and control C57Bl/6 J mice (Ctl) were investigated. Mineralization process was assessed using sodium fluoride ([18F]NaF) PET, and MR imaging combined with intravenous injection of MPIO-αVCAM-1 was used to evaluate endothelial activation. Micro- and macrocalcifications were evaluated by flame atomic absorption spectroscopy and von Kossa staining, respectively. Results Ur mice showed an active and sustained mineralization process compared to Ctl mice ( p = 0.002) using [18F]NaF PET imaging. Calcium plasma level was increased in Ur (2.54 ± 0.09 mM, n = 17) compared to NUr and Ctl mice (2.24 ± 0.01, n = 22, and 2.14 ± 0.02, n = 27, respectively; p < 0.0001). Likewise, vascular calcium content was increased in Ur (0.51 ± 0.06 μg Ca 2+ per milligram of dry weight aorta, n = 11) compared to NUr (0.27 ± 0.05, n = 9, p = 0.013) and Ctl (0.28 ± 0.05, n = 11, p = 0.014). Ur mice also had a higher inflammatory state using MPIO-αVCAM-1 MR ( p global = 0.01, post hoc analysis Ur vs. Ctl p = 0.003) associated with increased VCAM-1 expression ( p global = 0.02). Aortic remodeling at the level of the brachiocephalic trunk, brachiocephalic trunk itself, and aortic arch in Ur mice was also demonstrated using MR. Conclusions Preclinical molecular imaging allowed in vivo characterization of the early phase of atherosclerosis. [18F]NaF PET showed early and sustained vascular mineralization in uremic ApoE −/− mice. MPIO-αVCAM-1 MR imaging demonstrated aortic endothelial activation, predominantly in segments with vascular remodeling.

Atherosclerosis Imaging with 18F-Sodium Fluoride PET

“…Regarding the question of which arterial wall compartment first experiences NaF-detectable microcalcifications, the Creager study demonstrated that NaF binds to microcalcifications formed by calcifying extracellular vesicles delivered from vascular smooth muscle cells, and it was shown in animal studies that exercise in hyperlipidemic mice (ApoE −/− ) with baseline aortic calcification is associated with a reduction in aortic NaF uptake, whereas the fold change in aortic calcification measured by CT remained constant [ 28 ]. Moreover, when comparing uremic ApoE −/− mice with non-uremic ApoE −/− mice or control mice, the heart and close-by aorta showed both early and sustained NaF-uptake, which may be associated with endothelial activation in segments with vascular remodeling [ 29 ]. The extent to which these studies in rodent models translate to humans is not clear.…”

Losartan Attenuates Atherosclerosis in Uremic Mice by Regulating Treg/Th17 Balance via Mediating PTEN/PI3K/Akt Pathway

“…Animal model was established as previously described [16]. Male C57BL/6J mice (6 weeks old, 20 ± 2 g) and C57BL/6J ApoE −/− mice were obtained from Jackson Laboratory (Bar Harbor, ME, USA) and then kept in pathogen-free individual cages under 12-h day/night cycle at the temperature of 15–25°C in 50–60% humidity.…”

VCAM-1 Target in Non-Invasive Imaging for the Detection of Atherosclerotic Plaques

“…In vivo: human adipose engraftment mouse model; Ex vivo: human coronary arteries [117] WD: Western Diet; HD: Hypercholesterolemic Diet. Otherwise, recently, Rucher et al coupled MPIO-VCAM-1 magnetic resonance with [ 18 F]NaF PET in an ApoE −/− mouse model with chronic renal failure in order to identify both endothelial activation and microcalcifications [96]. This preclinical investigation opens new perspectives for the evaluation of the dynamic process of atherosclerosis by helping understand the relationship between inflammation, early mineralisation, which is known to detect high risk plaques, and vascular remodelling observed in this murine model.…”