Spatiotemporal expression and localization of matrix metalloproteinas-9 in a murine model of thoracic aortic aneurysm.

摘要

OBJECTIVE: Matrix metalloproteinase-9 (MMP-9) has been widely described to play a critical role in aneurysm development. The goal of this study was to determine the spatiotemporal changes in MMP-9 expression and abundance in the early stages of aortic dilatation during the course of thoracic aortic aneurysm (TAA) formation in a mouse model. METHODS: In this study, TAAs were surgically induced in a transgenic reporter mouse strain expressing the beta-galactosidase (beta-gal) gene under control of the MMP-9 promoter. Terminal studies were performed during the early stages of TAA development at 1 week (n = 6), 2 weeks (n = 6), and 4 weeks (n = 6) post-TAA induction surgery. Changes in aortic outer diameter were determined in vivo by video micrometry. MMP-9 transcriptional activity (beta-gal staining) and protein content (immunohistochemistry) were quantified at each time point and expressed as a percentage of unoperated reference control mice (n = 6). RESULTS: Aortic dilatation was evident at 1 week and reached maximal size at 2 weeks (21% +/- 6% increase from baseline, P < .05). MMP-9 transcriptional activity was detected at 1 week post-TAA induction (722% +/- 323%, P = .19), reached a maximum within the adventitia at 2 weeks (1770% +/- 505%, P < .05), and returned to baseline by 4 weeks (167% +/- 47%, P = .21). MMP-9 transcription at 2 weeks colocalized with fibroblasts and smooth muscle cells. MMP-9 protein content within the aortic adventitia was increased at 2 weeks post-TAA induction (413% +/- 124%, P < .05) and remained elevated at 4 weeks (222% +/- 41%, P < .05). MMP-9 staining was most intense at the adventitial-medial border and could be detected throughout the elastic media. CONCLUSIONS: These findings demonstrate a unique spatiotemporal pattern of MMP-9 transcriptional activation and protein content in the developing TAA. Colocalization studies suggest that early dilatation may be driven in part by MMP-9 produced by endogenous cells residing within the aortic vascular wall.