Spatiotemporal expression and localization of matrix metalloproteinas-9 in a murine model of thoracic aortic aneurysm.
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.
Jones
Jeffrey A
JA
Department of Surgery, Division of Cardiothoracic Surgery, Medical University of South Carolina, Charleston, SC 29425, USA.
Barbour
John R
JR
Lowry
Abigail S
AS
Bouges
Shenikqua
S
Beck
Christy
C
McClister
David M
DM
Mukherjee
Rupak
R
Ikonomidis
John S
JS
D000818:Animals; D001013:Aorta, Thoracic / Q000201:enzymology* / Q000473:pathology; D017545:Aortic Aneurysm, Thoracic / Q000201:enzymology* / Q000473:pathology; D004195:Disease Models, Animal; D018450:Disease Progression; D005347:Fibroblasts / Q000201:enzymology; D015971:Gene Expression Regulation, Enzymologic; D017930:Genes, Reporter; D007150:Immunohistochemistry; D020780:Matrix Metalloproteinase 9 / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008822:Mice, Transgenic; D018715:Microscopy, Video; D009131:Muscle, Smooth, Vascular / Q000201:enzymology; D011401:Promoter Regions, Genetic / Q000235:genetics; D012333:RNA, Messenger / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013997:Time Factors; D014158:Transcription, Genetic; D015854:Up-Regulation; D001616:beta-Galactosidase / Q000235:genetics
D012333:RNA, Messenger; D001616:beta-Galactosidase; D020780:Matrix Metalloproteinase 9