|Year : 2019 | Volume
| Issue : 3 | Page : 50-55
Animal models in experimental abdominal aortic aneurysm
Fang Xu1, Xu Zhang2, Yuehong Zheng2
1 Department of Vascular Surgery, Chinese Academy of Medical Sciences and Peking Union Medical College Hospital, Beijing; Graduate School, Hebei North University, Zhangjiakou, Hebei, China
2 Department of Vascular Surgery, Chinese Academy of Medical Sciences and Peking Union Medical College Hospital, Beijing, China
|Date of Submission||15-Jul-2020|
|Date of Decision||15-Jul-2020|
|Date of Acceptance||16-Jul-2020|
|Date of Web Publication||25-Aug-2020|
Prof. Yuehong Zheng
Department of Vascular Surgery, Chinese Academy of Medical Sciences and Peking Union Medical College Hospital, Beijing 100730
Source of Support: None, Conflict of Interest: None
Abdominal aortic aneurysm (AAA) is a prevalent and potentially life-threatening disease. Many animal models have been developed to simulate the natural history of the disease or test preclinical endovascular devices and surgical procedures. The aim of this review is to describe different methods of AAA induction in animal models and report on the effectiveness of the methods described in inducing an analog of a human AAA. The PubMed database was searched for publications with titles containing the following terms “animal” or ''animal model(s)'' and keywords “research,” “aneurysm(s),” “aorta,” “pancreatic elastase,” “angiotensin,” “AngII” “calcium chloride” or “CaCl2.” Starting date for this search was set to 2010. We focused on animal studies that reported a model of aneurysm development and progression. A number of different approaches of AAA induction in animal models have been developed, used, and combined since the first report in the 1960s. Although specific methods are successful in AAA induction in animal models, it is necessary that these methods and their respective results are in line with the pathophysiology and the mechanisms involved in human AAA development. A researcher should know the advantages or disadvantages of each animal model and choose the appropriate model.
Keywords: Abdominal aortic aneurysm, angiotensin II, animal models, BAPN, calcium chloride, porcine pancreatic elastase
|How to cite this article:|
Xu F, Zhang X, Zheng Y. Animal models in experimental abdominal aortic aneurysm. Transl Surg 2019;4:50-5
| Introduction|| |
Abdominal aortic aneurysm has been defined, it is reported that focal dilation ≥1.5 times the diameter of the normal aorta., The prevalence of AAA, overall population ranges between 3% and 7%, is increasing among the age from 55 to 60 years in recent years. AAA is associated with inflammation, vascular smooth muscle cell (VSMC) apoptosis, oxidative stress, and extracellular matrix degradation., The risk factors for AAA include male gender, smoking history, advanced age, family history, dyslipidemia, and hypertension., It is necessary to establish an animal model that is short in time, reasonable in cost, and highly similar to human pathophysiology. There is still no mature program that simulated perfectly human pathobiology to build animal models. This study summarized and improved the current AAA schemes in recent years, and proposed innovative views on AAA model construction, providing a new and efficient method for AAA clinical research, and an ideal research carrier for clinical transformation and scientific research. At home and abroad, the construction methos include that gene editing, calcium chloride (CaCl2) compress and elastic protein enzyme and angiotensin II (AngII) infusion method as well as a variety of joints and so on. Understanding the advantages and disadvantages of several kinds of modeling methods, the animal model of physiology is highly similar to the characteristics of the human vascular disease, the aim of this review is to provide insight on AAA animal model sececting approaches.
| Abdominal Aortic Aneurysm Induced by Angiotensin Ii|| |
The most common method, induced AAA, is intraluminal perfusion or subcutaneous pump. The first, in the 2000s, was reported that AngII can promote AAA process and progress, which revealed two characteristics: remodeled adventitia and medial break. AngII stimulates an inflammatory response in the vessel wall, independently of changes in blood pressure alone., Jun et al. investigated that PM2.5 promotes AAA formation by mini-osmotic pumps filled with AngII for 4 weeks; the result showed that the AAA incidence was 94.7%. The pathological changes of AAA including elastin matrix merallopreteinase (MMP) and Monocyte chmotactic protein 1 (MCP-1) was found. Zhang et al. determined, undergoing 28 days, that SIRT1 influences macrophage polarization and promotes AngII-induced AAA formation in mouse macrophage-specific knockout of sirtuin 1 (SIRT1). Meanwhile, increased degradation of elastin with vascular wall was also found. In a study, the researchers used AngII and CaCl2 for 4 weeks to explore SIRT1 related to AAA-related pathological changes. 1000 ng/kg/min AngII was implanted subcutaneously into apolipoprotein E-deficient (ApoE) for 4 weeks by Sun et al. Angelov et al. compared the prevalence, severity, and histopathology of AngII-induced AAA among control mice. A study concluded that AngII-infused mice are more clinically relevant for the study of aortic dissections than for the study of AAAs. Containing AngII (800 ng/kg/min) with osmotic mini-pump implanted into ApoE−/− mice background to construct well-characterized mouse model of AAA, Verhoeff–Van Gieson staining showed extensive disruption and degradation of the elastic lamina in the aortas of AAA. The role of systemically administered CAR-DCN (decorin) in AAA progression and rupture was assessed in apolipoprotein E knockout mouse model infused with AngII for 28 days to induce AAA formation. Hou et al. reported that AAA model was established by continuous infusion of 1000 ng/kg/min of AngII in ApoE−/− mice background by subcutaneous osmotic mini-pumps for 4 weeks to study the role and underlying mechanism of licochalcone A in AAA. The role of anti-microRNA-712 or anti-microRNA-205 in AAA development was conducted by AngII infusion in ApoE−/− mice (1 μg/kg/min). AngII was was also applied to establish AAA and ventricular hypertrophy (VH) animal models. ApoE−/− (apolipoprotein E deficient) mice were infused subcutaneously with AngII (1000 ng/kg/day; 4 weeks) to induce AAA and VH. Hong Lu et al. determine whether infection of normocholesterolemic mice with an adeno-associated viral vector expressing a gain-of-function mutation of mouse proprotein convertase subtilisin/kexin type 9 increased AngII-induced AAAs for 4 weeks. Apolipoprotein E-deficient (ApoE−/−) mice were infused with AngII for 7 days to explore the role of CD40L in aneurysm formation. Male apolipoprotein E deficient (ApoE−/−) mice (8 weeks of age) received AngII (1000 ng/kg/min) via implanted with subcutaneous osmotic mini pumps to investigate the effect of cortistatin administration in AngII-induced AAA. Umebayashi et al. evaluated the effects of cilostazol on AngII-induced AAA formation (1000 ng/kg/min) for 4 weeks. AAA was induced by infusion of 1000 ng/kg/min AngII via subcutaneously implanted mini-osmotic pumps for 28 days by Zhai et al.; they found that ursolic acid (UA) decreased the incidence of AngII-induced AAA in mice, UA can be alleviated the degradation of elastin fibers and inflammation and decreased the expression of MMP-2,9.
| Abdominal Aortic Aneurysm Animal Models Induced by Local Application of Calcium Chloride|| |
This method is more mature and stable and is widely used in the construction of AAA. AAA animal models induced by CaCl2 shows typical AAA pathological characteristics: calcification, inflammatory cell infiltration, oxidative stress, neovascularization, elastin degradation, and VSMC cell apoptosis; CaCl2-induced AAA does not display aortic thrombus, atherosclerosis, and rupture which are classical features of human AAA. Hashizume et al. examined whether vascular inflammation affects synaptic and cognitive dysfunction using AAA mouse model with AngII infusion combined with local CaCl2 application for 4 weeks; this model showed that vascular inflammation is a pathological hallmark caused by macrophage infiltration and increased secretion or expression of inflammatory cytokines. Intermedin (IMD), as a regulator of oxidative stress, was researched whether can attenuate AAA progression using AngII-induced ApoE−/− mouse and CaCl2-induced C57BL/6J mouse model; ultrasonography, hematoxylin and eosin staining, and Verhoeff–Van Gieson staining showed that IMD1–53 significantly decreased the enlarged aortas and oxidative stress, inflammation, VSMC cell apoptosis, and MMP activation. Using the AngII-induced hypercholesterolemic for 4 weeks and the 0.25 mol/L CaCl2-induced normocholesterolemic mouse model of AAA application, a small cotton strip was soaked in the solution for 15 min. Son et al. investigated the effects of testosterone on AAA formation using a murine AAA model induced by CaCl2 application and AngII infusion. It is further confirmed that microRNA-33 deletion attenuated AAA formation, utilizing mouse models of AngII- and CaCl2-induced AAA. To verify myeloperoxidase in AAA pathogenesis and the role of taurine in AAA patient, the researcher was established animal models combined with three approaches including AngII infusion 28 days, perfused with porcine pancreatic elastase (PPE) and 0.5 mol/L of CaCl2 applied to the infrarenal aortic adventitial surface for 15 min. A study suggested that a small piece of gauze soaked in 0.5M CaCl2 was applied perivascularly for 10 min, followed by application of phosphate-buffered saline-soaked gauze for 5 min. Alex Lederman conducted endovascular model of AAA induction by compared CaCl2-induced AAA to elastase-treated aneurysmal dilation; the result showed that the CaCl2 group developed aneurysmal dilation and calcification of the aortic wall, whereas elastase-treated animals showed only a dilated segment. Di Gennaro et al. were analysed the role of cysteinly leukotriene receptor 1 antagoism in AAA, they constructed AAA animal models by three approaches AngII-induecd AAA, PPEinduced AAA and Cacl2-indeced AAA; 0.25 M CaCl2 was applied to the external surface of the aorta using a cotton applicator cut to size for 15 min to investigate CD95 ligand that contributes to AAA progression by modulating inflammation. AAA was induced with administration of intraluminal elastase and extraluminal CaCl2 in male rats. The aorta was wrapped in gauze soaked with 0.5 mol/L CaCl2 for 20 min combined with simultaneous administration of elastase. Bi et al. established a rabbit AAA animal model by the method of CaCl2 combined with elastase. AAA created by using a combination of periaortic CaCl2 and elastase incubation is simple and effective to perform and is valuable for elucidating AAA mechanisms and therapeutic interventions in experimental studies. Tanaka et al. utilized isotonic elastase and external application of CaCl2 under the kidney to establish a rat AAA animal model.
| β-Aminopropionitrile-Induced Abdominal Aortic Aneurysm Animal Model|| |
β-Aminopropionitrile (BAPN) is a compound known to cause aortic aneurysms by inhibiting lysyl oxidase, a collagen cross-linking enzyme. Wild-type 8-week-old C56BL/6 male mice were divided into three groups: BANP group, elastase group, BANP+ elastase group. Cytokine levels such as MMP-9, interleukin (IL)-1β, and MCP-1 in the BAPN+ elastase group were higher than in the elastase group on day 7. Eventually, compared with the elastase group, the BANP+ elastase group had a higher AAA formation rate and had a considerable thrombus formation and rupture rate at the advanced stages of AAA development, and some cytokines were higher than the elastase group on day 7, but the level was decreased baseline after 7 days. Cullen et al. compared BAPN plus surgery with surgery alone on AAA animal models; the result show that BAPN with the surgery group was significantly larger AAA than surgery alone; smooth muscle cells, M1 macrophages, MMP-2, and multiple pro-inflammatory cytokines were significantly higher than only surgery. By utilizing a relatively new mouse model that combines a surgical application of topical elastase to cause abdominal aortic expansion, and a lysyl oxidase inhibitor, BAPN, in the drinking water, we were able to create large AAAs that expanded over 28 days. The result could help lay the groundwork for improving insight into clinical prediction of AAA expansion. C57BL/6 mice were infused with AngII and BAPN to induce AAA aimed to determine their hypothesis that inhibition of epidermal growth factor receptor by erlotinib prevents AAA formation. AngII and BAPN were administrated subcutaneously in 7-week-old C57BL/6J mice using an osmotic mini-pump for 4 weeks to generate a wild-type mouse model of aortic aneurysm to assess the protective effect of azelnidipine, a new calcium channel blocker, against the progression of the AA independent of its antihypertensive effect. The effect of IL-27R deficiency on AAA development was confirmed in AAA models induced by topical application of elastase combined with administration of 0.2% BAPN in drinking water.
| Elastase-Induced Abdominal Aortic Aneurysm Model|| |
A model of AAA was established by infusion of PPE into mice lacking MMP-9/12, and then, they showed that transient elastase perfusion of the mouse aorta results in delayed aneurysm development that is temporally associated with transmural mononuclear inflammation, increased local production of several elastolytic MMPs, and progressive destruction of the elastic lamellae. Bi et al. established a New Zealand rabbit aortic dissection animal model by infusion of PPE, and the rabbit AAA model induced via topical application of porcine elastase at 10 units/μl for 30 min appears easy and simple, with shorter induction and more rapid aortic dilation. A work by Pope et al. studied that the effect of elastase induction on AAA to confirm resolvin can attenuate murine AAA formation through alterations in macrophage polarization and cytokine expression; the aorta was perfused with 0.45 U/ml solution of PPE in 0.9% sodium chloride for 5 min. AAA was induced in WT C57BL/6 male mice, employing an established topical elastase AAA model. Osmotic pumps were implanted in mice 5 days before operation to create the model, administering either low dose (0.125 μg/day tamsulosin), high dose (0.250 μg/day tamsulosin), or vehicle treatments with and without 5 μl topical application of elastase. AAA was induced by local application of 1.5 U pancreatic elastase on the abdominal aortas of C57BL/6 mice to study whether grape-seed polyphenols have anti-AAA effects and what mechanism is involved. Wild-type 8–12-week-old C57BL/6 male mice and ApoE/mice were used in two models, respectively, topical elastase AAA model and AngII infusion model, to demonstrate the effects of resolvin D1 on AAA growth. Rabbits underwent extrinsic coarctation and received a 10-min elastase incubation in Group A and Group B on AAA to research hemodynamics and pathology. In 4 weeks, absorbable suture used in Group A was terminated by balloon dilation. Experimental AAA in mice was induced by aortic elastase (6 U/mg) perfusion to test the relationship of increased galectin-3 levels with AAA. AngII–perfusion ApoE−/− male mice and PPE perfusion C57BL/6 mice were induced AAA to research the role of T-helper 17 cells and IL-17A. The rats and Yucatan mini-pig were infused PPE to establish AAA animal models. Nie et al. explored the effect of different concentrations of elastase on the rate of AAA modeling. The comparison finally concluded that 100 U/mL elastase low-pressure perfusion can effectively establish AAA in rabbits, and the modeling rate is 102.5%–146.8%, and the mortality rate is the lowest. Using an established murine elastase-induced AAA model, Raaz et al. demonstrate that segmental aortic stiffening precedes aneurysm growth. AAAs were created in male C57BL/6J mice via intra-aortic elastase (30 μL of type I PPE) infusion that examined the pathogenic significance of vascular endothelial growth factor (VEGF)-A in experimental AAA and its receptor inhibition in aneurysm suppression; VEGF-A and its receptors contribute to experimental AAA formation by suppressing mural angiogenesis, MMP and VEGF-A production, myeloid cell chemotaxis, and circulating monocytes. Lareyre et al. test a hypothesis that blockade of transforming growth factor-β activity – a guardian of vascular integrity and immune homeostasis – would impair vascular healing in models of nondissecting AAA and would lead to sustained aneurysmal growth until rupture in the elastase-induced AAA model in mice. The study aimed to create an experimental model of enlarging AAA in rabbits to better mimic human aortic aneurysm disease which underwent extrinsic aortic stenosis below the right renal artery and received a 10-min incubation of 60 μl elastase (1 unit/μl). The result demonstrated that all aneurysms formed and enlarged progressively by 3 weeks in the aneurysm groups. However, diameter enlargement in Group A was significantly lower than that in Group B at 7 weeks. Experimental AAAs were created by transient intra-aortic PPE (30 mL Type 1) infusion to investigate metformin influence on the progression of AAA disease.
| Discussion|| |
This article summarizes the construction of AAA above the aspects for the period of AAA animal model, method, and cost. A variety of different animal models are subjected to either chemical or surgical induction of AAA. These animals vary from rodents (mice or rats) to larger animals, such as pigs and in some cases canines, the use of the latter still being controversial. Most union methods are used to build AAA models, which have a higher model formation rate than a single method and can shorten the time of construction. However, there are many disadvantages to using a single method to establish AAA, such as only expansion, not there is calcification or only calcification, and the expansion is not obvious. Elastase model is the common approach to establish AAA animal models, the cost of elastase is lower than AngII-induced and is more shows classic pathology. The CaCl2-induced AAA model resembles many pathological features of human AAA, such as marked aortic calcification, inflammation, oxidative stress, MMP activity, neovascularization, elastin degradation, and VSMC apoptosis. The advantages of the CaCl2-induced AAA technique include: (1) it can be applied to wild-type mice making the assessment of transgenic rodent models more straight forward and rapid and (2) CaCl2-induced AAAs are usually developed in the infrarenal abdominal aorta, which is the most common location of human AAA. AngII-induced model is technically less challenging than the PPE model since there is no need for major surgical manipulation of mice. AngII perfusion needs effective micro-pumps, and animals tend to form suprarenal aneurysms. Therefore, the establishment of AAA should be converted to a minimally invasive field and established to be highly similar to human disease animal models, and give the best comfort to small animals, so as not to cause animal death and affect the entire experiment. Experimental aneurysm models can be a powerful tool to elucidate the pathogenesis of AAA. Targeted biological pathways may help slow the growth of AAA in the pathogenesis of AAA and may prevent the breakdown of AAA. To achieve these goals, it is important to have a reliable and reproducible animal model of AAAs that simulates real human aneurysms.
| Conclusion|| |
No perfect model of human AAA has yet been developed. It is, therefore, important to keep in mind the qualities of the different models and species present when designing AAA studies to use the best model to support the aim of the study. At present, establishment animal models of AAA highly similar to humans can unite mixture method such as AngII+BANP or CaCl2+ elastase. The complex means, such BAPN+AngII, are increasing important to create a highly similar with human AAA animal models.
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Conflicts of interest
There are no conflicts of interest.
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