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

ObjectiveMatrix 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.MethodsIn this study, TAAs were surgically induced in a transgenic reporter mouse strain expressing the β-galactosidase (β-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 (β-gal staining) and protein content (immunohistochemistry) were quantified at each time point and expressed as a percentage of unoperated reference control mice (n = 6).ResultsAortic 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.ConclusionsThese 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.

Clinical RelevanceThe detection of thoracic abdominal aneurysm (TAA) formation and progression remains clinically difficult to manage. TAA development is a multifactorial process influenced by both cellular and extracellular mechanisms that converge on common maladaptive signaling pathways that alter the vascular environment. Active remodeling of the vascular extracellular matrix has been directly implicated in aortic dilatation and aneurysm development, and multiple studies have shown that matrix metalloproteinase-9 (MMP-9) has a critical role in this process. Thus, the goal of this study was to define the spatiotemporal relationship between MMP-9 expression/abundance and the initiation of aortic dilatation in the developing TAA. Understanding when and where MMP-9 is expressed locally defines a therapeutic window during which disruption of MMP-9 activity may aid in attenuating TAA progression.