ReviewThe calcium chloride-induced rodent model of abdominal aortic aneurysm
Introduction
Aortic aneurysm is the general term for any dilation (aneurysm) of the aorta to greater than 1.5 times normal size [1]. Abdominal aortic aneurysm (AAA) represents a weakened and dilated region of the abdominal aorta usually affecting the infra-renal segment [2]. AAA has previously been reported to affect ∼5% men aged over 65 years [3], [4]. Recent studies suggest that AAA prevalence is decreasing. A recent large screening study in Sweden reported an AAA prevalence of 1.7% in 65-year-old men [5]. A recent epidemiological study in England and Wales suggests that AAA mortality is decreasing and AAA presentation is shifting to an older population of ≥75 years [6]. The pathological features of AAA include increased elastin degradation, vascular smooth muscle cell (VSMC) apoptosis, oxidative stress and inflammation [7], [8]. The risk of AAA rupture increases with increasing aortic diameter [9]. Mortality after AAA rupture is about 80% for those who reach hospital and ∼50% for those who undergo surgery [10], [11]. There is no established therapy for small AAAs [12]. Larger (greater than 5.5 cm in diameter) or symptomatic AAAs usually undergo open surgical or endovascular repair [13]. Both surgical repair methods have some limitations. Open surgery is associated with a significant peri-operative mortality and morbidity; while up to 20% patients who undergo endovascular repair require reintervention within 5 years [14].
AAA diagnosis is problematic because most aneurysms are asymptomatic until rupture. While ultrasound screening has been introduced in older males in some countries, the feasibility of continuing such programs is in question with the evidence suggesting that AAA incidence is decreasing [6]. There is therefore great current interest in identifying novel diagnostic markers and appropriate molecular targets for drug development [15]. The mechanisms underlying AAA initiation and progression remain incompletely understood, contributing to significant shortfalls in the diagnosis and management of AAA. Experiments using human biopsies and cells derived from these biopsies are helpful in providing information on end-stage AAA pathogenesis. Such studies are limited by the decreasing availability of samples from open AAA repair and the inherent difficulties in modelling in vivo pathology. Animal models enable the study of AAA pathogenesis in vivo.
One of the animal models used to investigate AAA is that induced by calcium chloride (CaCl2) [16], [17], and research employing this model has provided insight into the pathogenesis of AAA. The current systematic review describes the technical aspects, cellular and molecular features of this animal model and comments on the relevance of this model to human AAA.
Section snippets
The development of the CaCl2 model
Calcification of the human aorta is common in older adults [18], [19]. A study in which 582 aortic specimens from the proximal portion of the aortic arch were examined demonstrated that calcification of the aortic media starts in people younger than 19 years and that the presence and severity of calcification increases with age [19]. Intimal calcification is present in most patients who have atherosclerosis and more severe aortic calcification has been shown to predict worse long term outcome
Technical aspects of the CaCl2-induced AAA model
By searching the PUBMED database and hand searching of the reference lists of relevant articles we identified 23 articles which reported employing the CaCl2-induced AAA model in rodents and 6 articles which reported employing modifications of the CaCl2 method in rodents. The technical aspects of the CaCl2-induced AAA model employed in these 23 studies were similar. Briefly, after the animals were anesthetized, the fur on the abdomen was removed and a midline abdominal incision was performed.
Cellular and molecular features of the CaCl2-induced AAA model
Peri-aortic application of CaCl2 has a large range of effects on aortic endothelial cells (ECs) and VSMCs. Peri-aortic application of CaCl2 to the rat aorta increases endothelial permeability and induces VSMC apoptosis [44]. VSMCs isolated from AAAs induced by CaCl2 produce large amounts of MMP-2 and MMP-9 [40] and less collagen, tropoelastin, and matrix elastin, compared to healthy VSMCs [40]. These characteristics of VSMCs are typically found in VSMCs isolated from human AAA tissue [50], [51]
The relevant of the CaCl2-induced rodent AAA model to human AAA
This animal model share many pathological features with human AAA, including aortic calcification, inflammatory cell infiltration, oxidative stress, neovascularisation, elastin degradation and VSMC apoptosis [13], [17], [21], [24], [25], [28], [29], [32], [34], [35], [38], [39], [40], [41], [42], [43], [44], [74], [75], [76], [77], [78], [79], [80], [81] (Table 6). On the other hand, CaCl2-induced AAA does not display thrombus, atherosclerosis and rupture, which are important features of human
Conclusion
The CaCl2-induced AAA model resembles many pathological features of human AAA, such as marked aortic calcification, inflammation, oxidative stress, MMP activity, neovascularisation, elastin degradation and VSMC apoptosis. In addition, studies using this model have identified some molecules important for AAA development in rodents which may be relevant to human AAA. These molecules include JNK, PPAR-γ, CCR2, sPLA2-X and plasminogen. On the other hand, this model does not display intraluminal
Conflict of interest
The authors declare that they have no conflict of interest.
Acknowledgement
This work is funded by grants from the National Health and Medical Research Council (540404, 1021416) and the BUPA Foundation. JG holds a Practitioner Fellowship from the National Health and Medical Research Council, Australia (1019921) and a Senior Clinical Research Fellowship from the Queensland Government.
References (99)
- et al.
Suggested standards for reporting on arterial aneurysms. Subcommittee on reporting standards for arterial aneurysms, Ad Hoc Committee on reporting standards, Society for vascular surgery and North American Chapter, International Society for cardiovascular surgery
J Vasc Surg
(1991) Epidemiology of aortic aneurysm in the United States
J Clin Epidemiol
(1995)- et al.
Guidelines for the treatment of abdominal aortic aneurysms. Report of a subcommittee of the Joint Council of the American association for vascular surgery and society for vascular surgery
J Vasc Surg
(2003) - et al.
Lost to follow-up: a potential under-appreciated limitation of endovascular aneurysm repair
J Vasc Surg
(2007) - et al.
Animal models of abdominal aortic aneurysm and their role in furthering management of human disease
Cardiovasc Pathol
(2011) - et al.
Aortic calcification
Eur J Vasc Endovasc Surg
(2005) - et al.
Relation of infra-renal abdominal aortic calcific deposits and cardiovascular events in patients with peripheral artery disease
Am J Cardiol
(2010) - et al.
Murine aortic aneurysm produced by periarterial application of calcium chloride
J Surg Res
(2001) - et al.
Vascular smooth muscle cell peroxisome proliferator-activated receptor-gamma deletion promotes abdominal aortic aneurysms
J Vasc Surg
(2010) - et al.
Deletion of CCR2 but not CCR5 or CXCR3 inhibits aortic aneurysm formation
Surgery
(2007)
Resveratrol prevents the development of abdominal aortic aneurysm through attenuation of inflammation, oxidative stress, and neovascularization
Atherosclerosis
Doxycycline in patients with abdominal aortic aneurysms and in mice: comparison of serum levels and effect on aneurysm growth in mice
J Vasc Surg
In vivo optical molecular imaging of matrix metalloproteinase activity in abdominal aortic aneurysms correlates with treatment effects on growth rate
Atherosclerosis
Membrane-type 1 matrix metalloproteinase regulates macrophage-dependent elastolytic activity and aneurysm formation in vivo
J Biol Chem
MMP-12 has a role in abdominal aortic aneurysms in mice
Surgery
Influence of indomethacin in the rat aneurysm model
Ann Vasc Surg
A novel rat model of abdominal aortic aneurysm using a combination of intraluminal elastase infusion and extraluminal calcium chloride exposure
J Vasc Surg
Activation of transglutaminase type 2 for aortic wall protection in a rat abdominal aortic aneurysm formation
J Vasc Surg
Free-radical scavenger edaravone inhibits both formation and development of abdominal aortic aneurysm in rats
J Vasc Surg
Increased synthesis of matrix metalloproteinases by aortic smooth muscle cells is implicated in the etiopathogenesis of abdominal aortic aneurysms
J Vasc Surg
Short-term 20-mg atorvastatin therapy reduces key inflammatory factors including c-Jun N-terminal kinase and dendritic cells and matrix metalloproteinase expression in human abdominal aortic aneurysmal wall
Atherosclerosis
Association of statin prescription with small abdominal aortic aneurysm progression
Am Heart J
Current status of medical management for abdominal aortic aneurysm
Atherosclerosis
Mouse group X secretory phospholipase A2 induces a potent release of arachidonic acid from spleen cells and acts as a ligand for the phospholipase A2 receptor
Arch Biochem Biophys
Group X secretory phospholipase A(2) induces potent productions of various lipid mediators in mouse peritoneal macrophages
Biochim Biophys Acta
Group X secretory phospholipase A(2) augments angiotensin II-induced inflammatory responses and abdominal aortic aneurysm formation in apoE-deficient mice
Atherosclerosis
Elastin degradation in abdominal aortic aneurysms
Atherosclerosis
Models of arterial aneurysm: for the investigation of pathogenesis and pharmacotherapy–a review
Atherosclerosis
Aneurysmal wall calcification predicts natural history of small abdominal aortic aneurysms
Atherosclerosis
Angiogenesis in abdominal aortic aneurysms
Eur J Vasc Endovasc Surg
Elastin stabilization in cardiovascular implants: improved resistance to enzymatic degradation by treatment with tannic acid
Biomaterials
Abdominal aortic aneurysm: pathogenesis and implications for management
Arterioscler Thromb Vasc Biol
Endovascular aortic aneurysm repair in patients with the highest risk and in-hospital mortality in the United States
Arch Surg
Low prevalence of abdominal aortic aneurysm among 65-year-old Swedish men indicates a change in the epidemiology of the disease
Circulation
Changing epidemiology of abdominal aortic aneurysms in England and Wales: older and more benign?
Circulation
Site specificity of aneurysmal disease
Circulation
Pathophysiology and epidemiology of abdominal aortic aneurysms
Nat Rev Cardiol
Clinical practice. Small abdominal aortic aneurysms
N Engl J Med
A meta-analysis of 50 years of ruptured abdominal aortic aneurysm repair
Br J Surg
Mortality from ruptured abdominal aortic aneurysm in Wales
Br J Surg
Turning back the clock: regression of abdominal aortic aneurysms via pharmacotherapy
J Mol Med (Berl)
Biomarkers of AAA progression. Part 1: extracellular matrix degeneration
Nat Rev Cardiol
Mouse models of abdominal aortic aneurysms
Arterioscler Thromb Vasc Biol
Calcification of the media of the human aorta and its relation to intimal arteriosclerosis, ageing and disease
Am J Pathol
Impact of calcifications on patient-specific wall stress analysis of abdominal aortic aneurysms
Biomech Model Mechanobiol
Aneurysm of the rabbit common carotid artery induced by periarterial application of calcium chloride in vivo
J Clin Invest
Influence of hypercholesterolemia and adventitial inflammation on the development of aortic aneurysm in rabbits
Arterioscler Thromb Vasc Biol
Matrix metalloproteinases 2 and 9 work in concert to produce aortic aneurysms
J Clin Invest
Regression of abdominal aortic aneurysm by inhibition of c-Jun N-terminal kinase
Nat Med
Cited by (79)
Immune checkpoint programmed death-1 mediates abdominal aortic aneurysm and pseudoaneurysm progression
2021, Biomedicine and Pharmacotherapy