A novel murine elastase saccular aneurysm model for studying bone marrow progenitor-derived cell-mediated processes in aneurysm formation.

Abstract

Although there are several large-species animal models for saccular aneurysms, there is a need for a simple, reproducible saccular aneurysm model in mice. To develop a murine saccular aneurysm model, which replicates key characteristics that occur in the formation of human cerebral aneurysms. 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. 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. 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.