Figure - available via license: CC BY
Content may be subject to copyright.
Histological images of carotid artery from rat ferric chloride model. (a) Longitudinal section of rat carotid artery 20 minutes after initiation of 20% ferric chloride injury. Arterial wall and blood show marked degenerative or denaturation changes at site of injury (arrows), wall constriction, and brown color at blood-vessel interface. Hematoxylin eosin stain. (b) Higher magnification of attached thrombus (*) shows absence of cellular and fibrillar structures and rather homogeneous appearance. Hematoxylin eosin stain.
Source publication
Thrombus formation on a disrupted atherosclerotic plaque is a key event that leads to atherothrombosis. Because thrombus is induced by chemical or physical injury of normal arteries in most animal models of thrombosis, the mechanisms of thrombogenesis and thrombus growth in atherosclerotic vessels should be investigated in diseased arteries of appr...
Citations
... Using this rabbit model, a recent MRI study of atherosclerosis monitored plaque progression preceding stimulated plaque rupture with serial analysis in the same animal [41]. Each aorta typically has several plaques, each of which can be monitored over time, and the stable and vulnerable plaques can be differentiated at the end of the 3-month protocol by triggering [39,42]. Notably, the size of its aorta is similar to a human coronary artery [39,42]. ...
... Each aorta typically has several plaques, each of which can be monitored over time, and the stable and vulnerable plaques can be differentiated at the end of the 3-month protocol by triggering [39,42]. Notably, the size of its aorta is similar to a human coronary artery [39,42]. These unique features render this rabbit model an ideal testbed for survival in vivo IVPA imaging. ...
Intravascular photoacoustic (IVPA) imaging is a promising modality for quantitative assessment of lipid‐laden atherosclerotic plaques. Yet, survival IVPA imaging of the same plaque in the same animal is not demonstrated. Here, using a sheathed IVUS/PA catheter of 0.9 mm in diameter, we demonstrate MRI‐guided survival IVPA imaging of same plaque in an aorta of a well‐established rabbit model mimicking atherosclerosis in human patients. The IVUS/PA results were confirmed by histology. These advances open the opportunity to evaluate the effectiveness of a therapy that aims to reduce the size of atherosclerotic plaques and demonstrates the potential of translating the IVPA catheter into clinic for detection of lipid‐rich plaques that are at high risk for thrombosis.
... Therefore, this reduction might have directly or indirectly contributed to the lower amounts of neuronal cell death and ischemia-induced neurodegeneration in the treatment group because of the intact microvessels without microclots. Another important factor to consider, with an eye on future studies, is that the coagulation cascade in rabbits appears very similar to that seen in humans [40]. Therefore, these results might also be reflected in humans. ...
Early brain injury (EBI), delayed cerebral vasospasm (DCVS), and delayed cerebral ischemia (DCI) are common complications of subarachnoid hemorrhage (SAH). Inflammatory processes in the cerebrospinal fluid (CSF) are one of the causes for such complications. Our aim to study the effects of an IL-6 receptor antagonist (Tocilizumab) examines the occurrence of DCVS, neuronal cell death, and microclot formation in an acute SAH rabbit model. Twenty-nine New Zealand white rabbits were randomized into one of three groups as the SAH, SAH + Tocilizumab, and sham groups. In SAH groups, hemorrhage was induced by extracranial-intracranial arterial blood shunting from the subclavian artery into the cisterna magna under intracranial pressure (ICP) monitoring. In the second group, Tocilizumab was given once intravenously 1 h after SAH induction. Digital subtraction angiography was performed, and CSF and blood were sampled before and after (day 3) SAH induction. IL-6 plasma and CSF levels were measured. TUNEL, FJB, NeuN, and caspase-3 immunostaining were used to assess cell apoptosis, neurodegeneration, and neuronal cell death, respectively. Microclot formation was detected by fibrinogen immunostaining. Between baseline and follow-up, there was a significant reduction of angiographic DCVS (p < 0.0001) in the Tocilizumab compared with the SAH group. Tocilizumab treatment resulted in decreased neuronal cell death in the hippocampus (p = 0.006), basal cortex (p = 0.001), and decreased microclot formation (p = 0.02). Tocilizumab reduced DCVS, neuronal cell death, and microclot formation in a rabbit SAH model, and could be a potential treatment to prevent DCVS and DCI in SAH patients.
... It is an important research trend of blood coagulation that the influences of vascular geometric shape, blood flow and TF diffusion are taken into account [7]. The artery thrombosis with vascular stenosis have been studied through clinical researches [8], [9], animal experiments [10], [11], microfluidic devices [11], [12], and mathematical models [13]. Those studies demonstrate that the pathological vessel geometries can lead to extreme blood flows and are risk factors for thrombosis. ...
The computational model of thrombosis is of great importance that decides the simulation performance. In the present study, a hybrid particle-continuum model with plasma, vascular wall, and thrombus being continuous material and platelets being discrete particles, was developed to simulate the thrombus growth. In the computational model, the thrombus growth was reformulated as a novel continuous surface expansion problem implemented by level set method due to its capability of effectively handling the topological changes comprising splitting and merging, rather than a traditional particle accumulation problem. Additionally, a Gaussian-based function and distance regularization function, serving as speed functions to drive the thrombus growth, were proposed and compared in our study. Experiments demonstrated that the growing thrombus could retain the particle texture of platelets by both level set speed functions, while the distance regularization function performed better in improving computational complexity and surface tracking behaviors. Both simulations demonstrated better visuality in the progress of thrombosis, and the geometry shape of the virtual primary thrombi were similar to the realistic counterpart.
... These diagnostic methods can predict hemorrhagic disease to a certain extent, but in vitro single-factor monitoring ignores the physiologic flow shear environment of hemostasis problems. Some in vivo animal hemostasis models show the direct global process of hemostasis at the wound sites, but it is difficult to apply mechanistic research at the intercellular level, which is limited by the means of observation and variable control [17,18]. Owing to the recent advances in microfabrication technologies, microfluidic platforms have been extensively used for microscale biological and biochemical experiments, owing to their low cost, high throughput, and good biocompatibility [15,19]. ...
... Based on findings from in vitro perfusion experiments [10,22,24] and in vivo thrombosis models [18,26], multiple adhesion receptors and ligands are involved in platelet aggregation, the most important of which include vWF, fibrinogen, and integrin α IIb β 3 . Here, vWF is a large multimeric protein essential for platelet adhesion under arterial flow conditions. ...
Hemorrhage is the phenomenon of blood loss caused by vascular trauma or other pathological reasons, which is life-threatening in severe cases. Because microhemorrhage is difficult to visually monitor and pre-treat in vivo , it is necessary to establish in vitro prediction methods to study the hemostasis mechanism in different physiological environments. In this study, a microfluidic bleeding model was developed to investigate the effect of blood flow shear on microvascular hemostasis. The results indicated that the regulation of blood shear rate on platelet aggregation affected the growth and morphology of hemostatic thrombus, and finally regulated the process of hemostasis. This in vitro model is significant to studies on hemostatic mechanisms, a reliable prediction of microhemorrhages, and an adjustment of the treatment scheme.
... The fact that fibrin-rich thrombus was associated with poor TIMI flow grade may also be related to thrombus stability. Thrombus formation is probably regulated by local blood flow, vascular wall thrombogenicity, and blood content [19]. Slow movement of blood allows electrostatic interactions to promote RBC aggregation [17,20]. ...
As the degree of luminal narrowing increases, shear stress increases, and high shear stress is known to activate platelets. However, the relationship between the degree of luminal narrowing and the composition of thrombus in patients with plaque erosion has not been studied. A total of 148 patients with plaque erosion and thrombus detected by optical coherence tomography were divided into tertiles based on the minimum lumen area (MLA) at the culprit lesion. Thrombus was categorized as platelet-rich or fibrin-rich. Among 148 patients, 50 (34%) were in the mild stenosis group, 49 (33%) were in the moderate stenosis group, and 49 (33%) were in the severe stenosis group. The composition of thrombus was significantly different among the 3 groups (prevalence of platelet-rich thrombus was 60% in the mild stenosis group; 78% in the moderate stenosis group; and 84% in the severe stenosis group; P = 0.021). The pattern of fibrin-rich thrombus showed the opposite: 40%, 22%, and 16%, respectively. In the multivariate analysis, current smoking was independently associated with fibrin-rich thrombus (odds ratio [OR] 2.364 [95% CI 1.004–5.567], P = 0.049). This study demonstrated that platelet-rich thrombus was the predominant type of thrombus in plaque erosion. The prevalence of fibrin-rich thrombus was highest in the mild stenosis group.
... Mechanical endothelium injury is a standard strategy to induce hyperplasia in various animal models such as mice, rabbits or minipigs [9,10,17]. In the present study, the endothelial injury was induced by two different approaches in rabbits: first by overexpansion of a BMS in the right iliac artery and second with an inflated balloon in the contralateral left iliac artery. ...
... In agreement with the literature, under conventional diet and following injury, rabbits developed wall hyperplasia that is known to be associated with inflammation and smooth muscle proliferation rather than atherosclerotic plaques that can be observed in hyperlipidemic rabbits [9,17]. ...
... 11,12 TF (tissue factor) expression in intimal SMCs has been reported in a previous animal model of plaque erosion. 13 However, the detailed mechanisms of plaque erosion and subsequent thrombus formation are not fully understood. ...
... While triggering often provoked the formation of adherent thrombi, these sites rarely displayed plaque rupture characterized by a disrupted fibrous cap, a potential difference with human atherothrombosis, although plaque rupture has been previously described following this pharmacologic triggering procedure. [45][46][47] On the other hand, this finding of mural thrombosis at sites of defective endothelial barrier function enhances the relevance of the present findings to superficial erosion, an increasingly recognized cause of acute coronary syndromes. These results further agree with the findings on thrombosed lesions observed in myocardial infarction-prone atherosclerotic rabbits treated with a spasmogenic triggering regimen. ...
Background:
The role of local alterations in endothelial functional integrity in atherosclerosis remains incompletely understood. This study used nanoparticle-enhanced optical molecular imaging to probe in vivo mechanisms involving impaired endothelial barrier function in experimental atherothrombosis.
Methods and results:
Atherosclerosis was induced in rabbits (n=31) using aortic balloon injury and high-cholesterol diet. Rabbits received ultrasmall superparamagnetic iron oxide nanoparticles (CLIO) derivatized with a near-infrared fluorophore (CyAm7) 24 hours before near-infrared fluorescence imaging. Rabbits were then either euthanized (n=9) or underwent a pharmacological triggering protocol to induce thrombosis (n=22). CLIO-CyAm7 nanoparticles accumulated in areas of atheroma (P<0.05 versus reference areas). On near-infrared fluorescence microscopy, CLIO-CyAm7 primarily deposited in the superficial intima within plaque macrophages, endothelial cells, and smooth muscle cells. Nanoparticle-positive areas further exhibited impaired endothelial barrier function as illuminated by Evans blue leakage. Deeper nanoparticle deposition occurred in areas of plaque neovascularization. In rabbits subject to pharmacological triggering, plaques that thrombosed exhibited significantly higher CLIO-CyAm7 accumulation compared with nonthrombosed plaques (P<0.05). In thrombosed plaques, nanoparticles accumulated preferentially at the plaque-thrombus interface. Intravascular 2-dimensional near-infrared fluorescence imaging detected nanoparticles in human coronary artery-sized atheroma in vivo (P<0.05 versus reference segments).
Conclusions:
Plaques that exhibit impaired in vivo endothelial permeability in cell-rich areas are susceptible to subsequent thrombosis. Molecular imaging of nanoparticle deposition may help to identify biologically high-risk atheroma.
... Cholesterol causes atherosclerotic changes in the rabbit arterial intima, very similar to human atherosclerosis. Atherosclerotic lesions also develop in normolipidemic rabbits as a result of repeated, or continuous intimal injury by catheters or balloons, or by nitrogen exposure (66). ...
Traditionally, non-cancer diseases are not considered as health risks following exposure to low doses of ionizing radiation. Indeed, non-cancer diseases are classified as deterministic tissue reactions, which are characterized by a threshold dose. It is judged that below an absorbed dose of 100 mGy, no clinically relevant tissue damage occurs, forming the basis for the current radiation protection system concerning non-cancer effects. Recent epidemiological findings point, however, to an excess risk of non-cancer diseases following exposure to lower doses of ionizing radiation than was previously thought. The evidence is the most sound for cardiovascular disease (CVD) and cataract. Due to limited statistical power, the dose-risk relationship is undetermined below 0.5 Gy; however, if this relationship proves to be without a threshold, it may have considerable impact on current low‑dose health risk estimates. In this review, we describe the CVD risk related to low doses of ionizing radiation, the clinical manifestation and the pathology of radiation-induced CVD, as well as the importance of the endothelium models in CVD research as a way forward to complement the epidemiological data with the underlying biological and molecular mechanisms.
... The photochemical injury involves the intravenous administration of photo-reactive rose bengal to an exposed arterial segment that is then illuminated with green light (540 nm) delivered from a xenon lamp equipped with a heat-absorbing filter (Matsuno et al., 1991;Yamashita and Asada, 2011). Rose bengal accumulates in the lipid bilayer of endothelial and other types of cells (Saniabadi et al., 1995;Yamashita and Asada, 2011). ...
... The photochemical injury involves the intravenous administration of photo-reactive rose bengal to an exposed arterial segment that is then illuminated with green light (540 nm) delivered from a xenon lamp equipped with a heat-absorbing filter (Matsuno et al., 1991;Yamashita and Asada, 2011). Rose bengal accumulates in the lipid bilayer of endothelial and other types of cells (Saniabadi et al., 1995;Yamashita and Asada, 2011). Green light triggers a photochemical reaction in rose bengal that produces singlet oxygen and promotes the formation of other reactive oxygen species that damage the endothelium and initiate thrombus formation. ...
... However, illumination can potentiate platelet function (Inamo et al., 1996), and therefore such thrombus formation is composed of aggregated platelets (Furukoji et al., 2005). These considerably differ from physiological thrombus formation after plaque disruption in humans (Yamashita and Asada, 2011). ...
Animal models of atherosclerosis often present limitations of transferability, since important hallmarks of human disease are not completely reproduced in other species. Rabbits have been used in several approaches:
1) inbred strains: Watanabe hereditary hyperlipidemic animals which express a defect in the LDL receptor, 2) transgenic rabbits, which overexpress human lipoproteins, and first knock-out rabbits.
3) native New Zealand white rabbits (NZW) fed with cholesterol-rich diet for at least 8 weeks represent the quickest way to establish arteriosclerosis. Rabbits are arguably the most sensitive animal species to cholesterol overload.
Interventions in native or arteriosclerotic arteries are used to induce local thrombus formation, e.g. endothelial denudation or photochemical injury. In contrast to smaller animals, catheterisation of coronary arteries is feasible, whose external ligation serves to induce myocardial infarction.
As biological endpoints, arterial vasoreactivity/endothelial dysfunction can be studied in analogy to measurements of brachial artery vasomotion in humans in response to increasing doses of acetylcholine or volume challenges. Tissue fixation allows studying vascular morphology, plaque sizes and thrombi after local interventions. Macrophage and T lymphocyte invasion can be investigated histologically. Positron emission tomography (PET/MRI) offers to measure plaques and content in vivo serially in the same animals.
Local virally mediated gene transfer to atherosclerotic rabbit arteries has been established as a rapid and reproducible method to test interesting transgenes. Histological plaque features correspond well to alterations in patients (inflammation and lipid load). Thus, effects of any proteins can be studied directly in the arteriosclerotic disease background – much quicker than after germline transgenesis and cross-breeding.
