An animal-specific FSI model of the abdominal aorta in anesthetized mice

Recent research has revealed that angiotensin II-induced abdominal aortic aneurysm in mice can be related to medial ruptures occurring in the vicinity of abdominal side branches. Nevertheless a thorough understanding of the biomechanics near abdominal side branches in mice is lacking. In the current work we present a mouse-specific fluid-structure interaction (FSI) model of the abdominal aorta in ApoE(-/-) mice that incorporates in vivo stresses. The aortic geometry was based on contrast-enhanced in vivo micro-CT images, while aortic flow boundary conditions and material model parameters were based on in vivo high-frequency ultrasound. Flow waveforms predicted by FSI simulations corresponded better to in vivo measurements than those from CFD simulations. Peak-systolic principal stresses at the inner and outer aortic wall were locally increased caudal to the celiac and left lateral to the celiac and mesenteric arteries. Interestingly, these were also the locations at which a tear in the tunica media had been observed in previous work on angiotensin II-infused mice. Our preliminary results therefore suggest that local biomechanics play an important role in the pathophysiology of branch-related ruptures in angiotensin-II infused mice. More elaborate follow-up research is needed to demonstrate the role of biomechanics and mechanobiology in a longitudinal setting

ULTRASOUND EVIDENCE OF ATHEROGENESIS IN MOUSE LEMUR PRIMATES

International audienceIntroduction The grey mouse lemur is an interesting alternative to transgenic models for the study of normal and pathological ageing [1]: aged animals (>5 years old) spontaneously and progressively develop sensori-motor deficits, alterations of biological rhythms, of thermal regulation, of metabolism, as well as cognitive decline and cerebral atrophy [2]. We here report for the first time aged-related vascular abnormalities, as detected by ultrasound imaging (US) performed at different locations. Methods Twelve females of 1 to 8 years old were studied by ultrasound imaging (Vevo 770, Visual Sonic, with a 20-60Hz mechanical probe) in search for morphological and functional abnormalities of arterial walls at the level of the aortic arch and the common carotids. Total thickness (TT), intima-media thickness (IMT) and extra-media thickness (EMT, [3]) were measured by a blinded, experienced investigator. Pulsatility was expressed as the percentage of variation between the diastolic and systolic diameters. Nine animals underwent blood sampling for LDL subfraction analysis using the Lipoprint system (Quantimetrix). Heart, aorta and carotids of three animals were kept in formol and processed for histology. Results Focal thickenings of carotid walls were observed on B-mode images in 5 out of 6 old animals (Fig. 1). Systematic proximal-wall measurements on M-mode images showed significantly higher carotid TT, IMT and EMT in aged vs young animals, along with decreased pulsatility (Fig. 2). LDL analysis and histology are in progress. Conclusions Using different US indexes of vessel wall functionality [3], we report in vivo evidence of atherogenesis in aged mouse lemurs. Therefore, this species holds promise as a new primate model of atherosclerosis

Molecular imaging of liver inflammation using an anti-VCAM-1 nanobody

Abstract To date, a biopsy is mandatory to evaluate parenchymal inflammation in the liver. Here, we evaluated whether molecular imaging of vascular cell adhesion molecule-1 (VCAM-1) could be used as an alternative non-invasive tool to detect liver inflammation in the setting of chronic liver disease. To do so, we radiolabeled anti-VCAM-1 nanobody ( 99m Tc-cAbVCAM1-5) and used single-photon emission computed tomography (SPECT) to quantify liver uptake in preclinical models of non-alcoholic fatty liver disease (NAFLD) with various degree of liver inflammation: wild-type mice fed a normal or high-fat diet (HFD), FOZ fed a HFD and C57BL6/J fed a choline-deficient or -supplemented HFD. 99m Tc-cAbVCAM1-5 uptake strongly correlates with liver histological inflammatory score and with molecular inflammatory markers. The diagnostic power to detect any degree of liver inflammation is excellent (AUROC 0.85–0.99). These data build the rationale to investigate 99m Tc-cAbVCAM1-5 imaging to detect liver inflammation in patients with NAFLD, a largely unmet medical need

Targeted radionuclide therapy with RAFT-RGD radiolabelled with 90Y or 177Lu in a mouse model of αvβ3-expressing tumours

International audiencePurposeThe αvβ3 integrin plays an important role in tumour-induced angiogenesis, tumour proliferation, survival and metastasis. The tetrameric RGD-based peptide, regioselectively addressable functionalized template-(cyclo-[RGDfK])4 (RAFT-RGD), specifically targets the αvβ3 integrin in vitro and in vivo. The aim of this study was to evaluate the therapeutic potential of RAFT-RGD radiolabelled with β− emitters in a nude mouse model of αvβ3 integrin-expressing tumours.MethodsBiodistribution and SPECT/CT imaging studies were performed after injection of 90Y-RAFT-RGD or 177Lu-RAFT-RGD in nude mice subcutaneously xenografted with αvβ3 integrin-expressing U-87 MG cells. Experimental targeted radionuclide therapy with 90Y-RAFT-RGD or 177Lu-RAFT-RGD and 90Y-RAFT-RAD or 177Lu-RAFT-RAD (nonspecific controls) was evaluated by intravenous injection of the radionuclides into mice bearing αvβ3 integrin-expressing U-87 MG tumours of different sizes (small or large) or bearing TS/A-pc tumours that do not express αvβ3. Tumour volume doubling time was used to evaluate the efficacy of each treatment.ResultsInjection of 37 MBq of 90Y-RAFT-RGD into mice with large αvβ3-positive tumours or 37 MBq of 177Lu-RAFT-RGD into mice with small αvβ3-positive tumours caused significant growth delays compared to mice treated with 37 MBq of 90Y-RAFT-RAD or 37 MBq of 177Lu-RAFT-RAD or untreated mice. In contrast, injection of 30 MBq of 90Y-RAFT-RGD had no effect on the growth of αvβ3-negative tumours.Conclusion90Y-RAFT-RGD and 177Lu-RAFT-RGD are potent agents targeting αvβ3-expressing tumours for internal targeted radiotherapy

Reduction in myocardial infarct size at 48 hours after brief intravenous infusion of ATL-146e, a highly selective adenosine A2A receptor agonist

This study was undertaken to determine whether the myocardial infarct-sparing effect of ATL-146e, a selective adenosine A2A receptor agonist, persists without a rebound effect for at least 48 h and to determine the optimal duration of ATL-146e treatment in anesthetized dogs. Reperfusion injury after myocardial infarction (MI) is associated with inflammation lasting 24–48 h that contributes to ongoing myocyte injury. We previously showed that an ATL-146e infusion, starting just before reperfusion, decreased inflammation and infarct size in dogs examined 2 h after MI without increasing coronary blood flow. In the present study, adult dogs underwent 90 min of left anterior descending coronary artery occlusion. Thirty minutes before reperfusion, ATL-146e (0.01 μg·kg−1·min−1; n = 21) or vehicle (n = 12) was intravenously infused and continued for 2.5 h (protocol 1) or 24 h (protocol 2). At 48 h after reperfusion hearts were excised and assessed for histological risk area and infarct size. Infarct size based on triphenyltetrazolium chloride (TTC) staining as a percentage of risk area was significantly smaller in ATL-146e-treated vs. control dogs (16.7 ± 3.7% vs. 33.3 ± 6.2%, P < 0.05; protocol 1). ATL-146e reduced neutrophil accumulation into infarcted myocardium of ATL-146e-treated vs. control dogs (30 ± 7 vs. 88 ± 16 cells/high-power field, P < 0.002). ATL-146e infusion for 24 h (protocol 2) conferred no significant additional infarct size reduction compared with 2.5 h of infusion. A 2.5-h ATL-146e infusion initiated 30 min before reperfusion results in marked, persistent (48 h) reduction in infarct size as a percentage of risk area in dogs with a reduction in infarct zone neutrophil infiltration. No significant further benefit was seen with a 24-h infusion