Tissue inhibitor of matrix metalloproteinases-1 impairs arterial neointima formation after vascular injury in mice.
The hypothesis that tissue inhibitor of metalloproteinases-1 (TIMP-1) plays a role in neointima formation was tested with the use of a vascular injury model in wild-type (TIMP-1(+/+)) and TIMP-1-deficient (TIMP-1(-/-)) mice. The neointimal area at 1 to 3 weeks after electric injury of the femoral artery was significantly higher in TIMP-1(-/-) as compared with TIMP-1(+/+) mice (0.012+/-0. 0015 versus 0.0033+/-0.0008 mm(2) at 1 week, P<0.005). The medial areas were comparable, resulting in intima/media ratios that were significantly larger in TIMP-1(-/-) as compared with TIMP-1(+/+) arteries (1.2+/-0.22 versus 0.39+/-0.08 at 1 week, P<0.005). Nuclear cell counts in cross-sectional areas of the intima of the injured region were higher in TIMP-1(-/-) as compared with TIMP-1(+/+) arteries (138+/-15 versus 69+/-8 at 1 week, P<0.005). Immunocytochemical analysis revealed that alpha-actin-positive smooth muscle cells (SMCs) at 2 weeks after injury were more abundant in the intima of TIMP-1(-/-) arteries than in that of TIMP-1(+/+) arteries, whereas after 3 weeks the intimal cell population consisted mainly of SMCs in both genotypes. In in vitro scrape-wounding assays, SMCs of TIMP-1(-/-) mice migrated faster than those of TIMP-1(+/+) mice. Zymography of arterial extracts revealed a higher active matrix metalloproteinase (MMP)-2 level at 1 to 3 weeks after injury in TIMP-1(-/-) arteries, whereas active MMP-9 was only detected in TIMP-1(-/-) arteries at 1 week after injury. These data are compatible with a role of TIMP-1 in the impairment of SMC migration and neointima formation after vascular injury, as a result of inhibition of MMP activity.
Lijnen
H R
HR
Center for Molecular and Vascular Biology, University of Leuven, Belgium. roger.lijnen@med.kuleuven.ac.be
Soloway
P
P
Collen
D
D
D000818:Animals; D002455:Cell Division; D002465:Cell Movement; D005260:Female; D005263:Femoral Artery / Q000473:pathology* / Q000503:physiopathology; D007150:Immunohistochemistry; D008297:Male; D051379:Mice; D019715:Tissue Inhibitor of Metalloproteinase-1 / Q000502:physiology*; D017539:Tunica Intima / Q000473:pathology* / Q000502:physiology
D019715:Tissue Inhibitor of Metalloproteinase-1