Mouse Models of Abdominal Aortic Aneurysms

Abstract

Abstract-Many mouse models of abdominal aortic aneurysms have been developed that use a diverse array of methods for producing the disease, including genetic manipulation and chemical induction. These models could provide insight into potential mechanisms in the development of this disease. Although experimental studies on abdominal aortic aneurysms (AAAs) have used a variety of mammalian and avian approaches, there is an increasing reliance on the use of mice. The models recapitulate some facets of the human disease including medial degeneration, inflammation, thrombus formation, and rupture. Most of the mouse models of AAA are evoked either by genetically defined approaches or by chemical means. The genetic approaches are spontaneous and engineered mutations. These include defects in extracellular matrix maturation, increased degradation of elastin and collagen, aberrant cholesterol homeostasis, and enhanced production of angiotensin peptides. The chemical approaches include the intraluminal infusion of elastase, periaortic incubations of calcium chloride, and subcutaneous infusion of AngII. A common feature of these models is the reduction of AAA incidence and severity by the prophylactic administration of matrix metalloproteinase (MMP) inhibitors or genetically engineered deficiencies of specific members of this proteolytic protein family. The validation of mouse models of AAAs will provide insight into the mechanisms of progression of the human disease.

Overexpression of PAI-1 prevents the development of abdominal aortic aneurysm in mice

“…It was known that MMPs played an important role in aneurysm development. 42,43 As the matrix protein degradation and subsequent weakening of the aortic wall are the chief features of AAA, the association of MMP activities and aneurysm has been established by many studies both in animal models 4,44 and in human. 45 MMPs are produced as zymogens mostly by activated macrophages in the vascular wall.…”

Creating a model of diseased artery damage and failure from healthy porcine aorta

“…This results in the elastin-collagen interaction altering and the stiffer collagen fibres being recruited at smaller deformations, leading to an observed stiffening of the arterial wall. Whilst in aneurysm formation, the characteristic ballooning is also widely attributed to loss of elastin and a resulting loss of stiffness in the artery [12,13]. In atherosclerosis, changes in elastin and collagen structure again weaken the medial and intimal layers [14,15,16].…”

Tissue Engineering and Regenerative Strategies to Replicate Biocomplexity of Vascular Elastic Matrix Assembly

“…Here, there are additional deterrents to elastic matrix synthesis, which include (1) switch of a subset of SMCs to a diseased phenotype characterized by poor elastogenicity compared to even healthy SMCs, 25 (2) diminished production of crosslinking enzymes and/or their impaired action, and (3) enhanced local production and activity of elastolytic enzymes by both recruited inflammatory cells and SMCs. 26 Together, these events reduce net accumulation of new elastin deposits and disrupt new and pre-existing elastic matrix structures, which would serve as nucleation sites for growth of new elastic fibers. 13 …”