Abstract WP346: A Cost-effective and Reproducible Mouse Model of Intracranial Aneurysm: Renal Hypertension and Local Hemodynamic Change Combined With Elastase Infusion

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Introduction: The study of animal models of intracranial aneurysms (IA) can improve our understanding of the IA pathogenesis and identify the potential pharmaceutical targets. Although a variety of mouse models of IA have been described, all the models have their limitations. We here modified the current models and established a cost-effective and reproducible mouse model that recapitulates the key features of human IA. Methods: In adult C57black/6 male mice, the left common carotid arteries and the left renal arteries were ligated with high salt diet. One week later, 35 mU elastase was stereotactically injected into the right basal cistern. The animals were closely monitored each day for any neurological symptoms until the end of the study. All asymptomatic mice were euthanized 4 weeks after stereotactic injection and the circle of Willis (COW) was inspected under microscope for the presence of aneurysm and/or signs of rupture. Histological analyses were then performed to evaluate the pathological features of IA. Quantitative real-time PCR was employed on COW tissue to compare the expression of IA-pathogenesis associated genes between IA-inducing group and sham operative controls group. Results: All of the mice in the IA-inducing group were developed various aneurysmal changes within COW (n=40). A total of 67.5% (27/40) of the mice were successfully induced saccular IA (sIA) and 11% (3/27) had ruptured aneurysms. The average sIA number for each mouse is 1.4 (38/27). Histologically, aneurysms observed in this model closely resembled human IA including fragmentation of internal elastic lamina, thinning or discontinuities of the smooth muscle cell layer, and F4/80 positive macrophage infiltration within the aneurysm wall. Gene expression assay revealed that IA induction significantly increased expression of inflammation ( NF-κBp65, TNF-α, IL-1β, IL-8 ), matrix remodeling ( MMP-2, TIMP-3 ), EC marker ( Vinculin ) and VSMC marker ( KIF5 ) genes. Conclusion: This model can serve as a useful tool for future studies that utilize various inhibitors, knockout mice, or transgenic mice to test how specific molecules and pathways influence IA development.