A Novel Murine Elastase Saccular Aneurysm Model for Studying Bone Marrow Progenitor-Derived Cell–Mediated Processes in Aneurysm Formation

Abstract

BACKGROUND: Although there are several large-species animal models for saccular aneurysms, there is a need for a simple, reproducible saccular aneurysm model in mice. OBJECTIVE: To develop a murine saccular aneurysm model, which replicates key characteristics that occur in the formation of human cerebral aneurysms. METHODS: Elastase is applied extravascularly to the right common carotid artery. We induced saccular aneurysm formation by our method in C57BL/6 mice (n = 30). Aneurysms and control arteries (left common carotid arteries) were harvested at 1 week, 2 weeks, and 3 weeks postinjury (n = 10 for each time point), measured, and stained for elastin content. To demonstrate BMP-derived cell recruitment to the aneurysms, bone marrow from UBC-gfp transgenic mice was transplanted into irradiated C57BL/6 recipients to create C57BL/6.gfp chimeras. Additionally, bone marrow from DsRed transgenic mice was transplanted into irradiated C57BL/6 recipients to create C57BL/6.DsRed chimeras, and bone marrow from B5/EGFP transgenic mice was transplanted into irradiated FVB recipients to create FVB.gfp chimeras. The elastase injury or sham operations were performed in the C57BL/6.gfp, C57BL/6.DsRed, and FVB.gfp chimeras. Aneurysms and sham vessels were harvested at 3 weeks and examined for BMP-derived cell recruitment. Additionally, aneurysms were stained for matrix metalloproteinase-9, which is overexpressed in human cerebral aneurysm tissue. RESULTS: Aneurysms consistently demonstrated significant loss of elastin in the vessel wall and had significantly larger diameters than control vessels (591 +/- 238 microm vs 328 +/- 61 microm; P = .003 for aneurysms 3 weeks postinjury). Aneurysms from C57BL/6.gfp, FVB.gfp, and C57BL/6.DsRed chimeras consistently revealed significant BMP-derived cell recruitment in the aneurysm wall that was not seen in sham-operated vessels nor in control left common carotid arteries. Aneurysms demonstrated overexpression of matrix metalloproteinase-9. CONCLUSION: We describe a novel murine elastase saccular aneurysm model that replicates the histopathology and BMP-derived cell-mediated processes that will be a valuable instrument for studying the cell-mediated processes in cerebral aneurysm formation.