title: Targeted disruption of the matrix metalloproteinase-9 gene impairs smooth muscle cell migration and geometrical arterial remodeling.
abstract: Matrix remodeling plays an important role in the physiological and pathological remodeling of blood vessels. We specifically investigated the role of matrix metalloproteinase (MMP)-9, an MMP induced during arterial remodeling, by assessing the effects of genetic MMP-9 deficiency on major parameters of arterial remodeling using the mouse carotid artery flow cessation model. Compared with remodeling of matched wild-type (WT) arteries, MMP-9 deficiency decreased intimal hyperplasia, reduced the late lumen loss, eliminated the correlation between intimal hyperplasia and geometric remodeling, and led to significant accumulation of interstitial collagen. Biochemical analysis of MMP-9 knockout (KO) arterial tissue and isolated smooth muscle cells (SMCs) confirmed the lack of MMP-9 expression or compensation by other gelatinases. To investigate potential mechanisms for the in vivo observations, we analyzed in vitro effects of MMP-9 deficiency on the migration, proliferation, and collagen gel contracting capacity of aortic SMCs isolated from MMP-9 KO and WT mice. Although proliferation was comparable, we found that MMP-9-deficient cells had not only decreased migratory activity, but they also had decreased capacity to contract collagen compared with WT cells. Thus, MMP-9 appears to be involved not only in degradation, but also in reorganization of a collagenous matrix, both facets being essential for the outcome of arterial remodeling. Our results also establish MMP-9 as an attractive therapeutic target for limiting the effects of pathological arterial remodeling in restenosis and atherosclerosis.
authors.affiliation: Division of Cardiology, Dept of Medicine, Emory University School of Medicine, Atlanta, Ga 30322, USA. zgalis@emory.edu
authors.forename: Zorina S
authors.initials: ZS
authors.lastname: Galis
authors.forename: Chad
authors.initials: C
authors.lastname: Johnson
authors.forename: Denis
authors.initials: D
authors.lastname: Godin
authors.forename: Richard
authors.initials: R
authors.lastname: Magid
authors.forename: J Michael
authors.initials: JM
authors.lastname: Shipley
authors.forename: Robert M
authors.initials: RM
authors.lastname: Senior
authors.forename: Eugen
authors.initials: E
authors.lastname: Ivan
mesh_terms: D000818:Animals; D002339:Carotid Arteries / Q000201:enzymology* / Q000473:pathology; D016893:Carotid Stenosis / Q000201:enzymology / Q000473:pathology; D002465:Cell Movement / Q000235:genetics; D003094:Collagen / Q000378:metabolism; D004195:Disease Models, Animal; D018450:Disease Progression; D004591:Electrophoresis, Polyacrylamide Gel; D004790:Enzyme Induction / Q000235:genetics; D005780:Gelatin / Q000737:chemistry / Q000378:metabolism; D018390:Gene Targeting; D007150:Immunohistochemistry; D008297:Male; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism; D020780:Matrix Metalloproteinase 9 / Q000172:deficiency* / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008815:Mice, Inbred Strains; D018345:Mice, Knockout; D009131:Muscle, Smooth, Vascular / Q000201:enzymology* / Q000473:pathology; D014654:Vascular Patency / Q000235:genetics
chemical_list: D005780:Gelatin; D003094:Collagen; D020778:Matrix Metalloproteinase 2; D020780:Matrix Metalloproteinase 9