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(Circulation Research. 1999;85:1186.)
© 1999 American Heart Association, Inc.

Integrative Physiology

Tissue Inhibitor of Matrix Metalloproteinases-1 Impairs Arterial Neointima Formation After Vascular Injury in Mice

H. R. Lijnen, P. Soloway, D. Collen

From the Center for Molecular and Vascular Biology (H.R.L., D.C.), University of Leuven, Belgium, and Roswell Park Cancer Institute (P.S.), Buffalo, NY.

Correspondence to H.R. Lijnen, Center for Molecular and Vascular Biology, University of Leuven, Campus Gasthuisberg, O & N, Herestraat 49, B-3000 Leuven, Belgium. E-mail roger.lijnen{at}med.kuleuven.ac.be

Abstract—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 mm² 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 -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.

Key Words: matrix metalloproteinase • TIMP • vascular injury • restenosis • gene-deficient mice

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