Endogenous animal models of intracranial aneurysm development: a review

Abstract

The pathogenesis and natural history of intracranial aneurysm (IA) remains poorly understood. To this end, animal models with induced cerebral vessel lesions mimicking human aneurysms have provided the ability to greatly expand our understanding. In this review, we comprehensively searched the published literature to identify studies that endogenously induced IA formation in animals. Studies that constructed aneurysms (i.e., by surgically creating a sac) were excluded. From the eligible studies, we reported information including the animal species, method for aneurysm induction, aneurysm definitions, evaluation methods, aneurysm characteristics, formation rate, rupture rate, and time course. Between 1960 and 2019, 174 articles reported endogenous animal models of IA. The majority used flow modification, hypertension, and vessel wall weakening (i.e., elastase treatment) to induce IAs, primarily in rats and mice. Most studies utilized subjective or qualitative descriptions to define experimental aneurysms and histology to study them. In general, experimental IAs resembled the pathobiology of the human disease in terms of internal elastic lamina loss, medial layer degradation, and inflammatory cell infiltration. After the early 2000s, many endogenous animal models of IA began to incorporate state-of-the-art technology, such as gene expression profiling and 9.4-T magnetic resonance imaging (MRI) in vivo imaging, to quantitatively analyze the biological mechanisms of IA. Future studies aimed at longitudinally assessing IA pathobiology in models that incorporate aneurysm growth will likely have the largest impact on our understanding of the disease. We believe this will be aided by high-resolution, small animal, survival imaging, in situ live-cell imaging, and next-generation omics technology.

Keywords: Animal model; Cerebral aneurysm; Intracranial aneurysm; Natural history; Review; Vascular disease.

Figure 1:. A flowchart detailing the literature survey that yielded the publications analyzed in this study.

In PubMed, we searched for published animal model studies of intracranial aneurysm, excluding those that used surgically created aneurysms (primarily to study medical devices). Furthermore, we manually excluded review articles, as well as other publications (i.e. commentaries on other articles) that did not fit our search criteria.

Figure 2:. A timeline of important milestones in IA model development.

For the most part, endogenous animal models of IA were developed from 1961 through the early 2000s. At the turn of the century there was an exponential growth in research focused on the pathogenesis of the disease. The top row shows noteworthy studies that utilized new methods to incite IA risk factors. The middle row highlights notable first uses of different animal species (many of which are still in use today, i.e. rats). The bottom row highlights the first use of different analytical technologies in the study of animal models of IA. Abbreviations: Ang II=Angiotensin II, angio.=angiography, BAPN= β-Aminopropionitrile, CFD=computational fluid dynamics, DOCA=deoxycorticosterone acetate, IA=intracranial aneurysm, KO=knock-out, SEM=scanning electron microscopy.

Figure 3:. Different methods used for IA model creation.

A diagram of a rat with annotations of different surgical and chemical manipulations performed to induce IA-associated risk factors. Abbreviations: BAPN= β-Aminopropionitrile, DOCA=deoxycorticosterone acetate.

Figure 4:. The different factors induced in endogenous animal models.

Each main risk factor (in bold) is represented by one oval (hemodynamic alteration - pink, hypertension - violet, estrogen deficiency - teal, connective tissue weakening - yellow, and genetic modification - green) The overlapping of ovals represents studies in which the respective methods were used in conjunction with each other. The number of studies using each method of IA induction is also indicated (italicization indicates the number for each combination of manipulations). The vast majority of the studies have implemented multi-modal models, with flow increase, hypertension, and connective tissue weakening as the predominant factors used.

Figure 5:. Aneurysm tissue examination methods in experimental models.

A graph indicating percentage each method was used in the literature. Model development studies tended to use corrosion casting and whole mount analysis, while mechanistic studies have strongly favored histology for analysis. Abbreviations: SEM=scanning electron microscopy.

Figure 6:. Features observed in endogenously-created animal aneurysms.

A graph indicating the percentage that each feature was observed in the literature. The three most common IA features are bulging, IEL loss, and medial thinning. Abbreviations: EC=endothelial cell, IEL=internal elastic lamina, SMC=smooth muscle cell.