Accelerated neointima formation after vascular injury in mice with stromelysin-3 (MMP-11) gene inactivation.
The hypothesis that stromelysin-3 (MMP-11), a unique member of the matrix metalloproteinase (MMP) family, plays a role in neointima formation was tested with the use of a vascular injury model in wild-type (MMP-11(+/+)) and MMP-11-deficient (MMP-11(-/-)) mice. Neointima formation 2 to 3 weeks after electric injury of the femoral artery was significantly enhanced in MMP-11(-/-) as compared with MMP-11(+/+) mice, in both mice of a pure 129SV genetic background (0.014 versus 0.0010 mm(2) at 2 weeks, P<0.001) and those of a 50/50 mixed 129SV/BL6 background (0.030 versus 0.013 mm(2) at 3 weeks, P<0.05). The medial areas were comparable, resulting in intima/media ratios that were significantly increased in MMP-11(-/-) as compared with MMP-11(+/+) arteries, in mice of both the 129SV (1. 0 versus 0.18, P<0.001) and mixed (1.5 versus 0.70, P<0.05) backgrounds. Nuclear cell counts in cross-sectional areas of the intima of the injured region were higher in arteries from MMP-11(-/-) mice than in those from MMP-11(+/+) mice (210 versus 48, P<0.001, in pure 129SV mice and 290 versus 150, P<0.01, in mice of the mixed genetic background). Immunocytochemical analysis revealed that alpha-actin-positive and CD45-positive cells were more abundant in intimal sections of MMP-11(-/-) mice. Degradation of the internal elastic lamina was more extensive in arteries of MMP-11(-/-) mice than in those of MMP-11(+/+) mice (39% versus 6.8% at 3 weeks, P<0. 005). The mechanisms by which MMP-11 could impair elastin degradation and cellular migration in this model remain, however, unknown.
Lijnen
H R
HR
Center for Molecular and Vascular Biology, University of Leuven, Leuven, Belgium. roger.lijnen@med.kuleuven.ac.be
Van Hoef
B
B
Vanlinthout
I
I
Verstreken
M
M
Rio
M C
MC
Collen
D
D
D000199:Actins / Q000032:analysis; D000818:Animals; D003251:Constriction, Pathologic; D004597:Electroshock; D004730:Endothelium, Vascular / Q000201:enzymology / Q000293:injuries* / Q000473:pathology*; D005263:Femoral Artery / Q000201:enzymology / Q000293:injuries* / Q000473:pathology*; D017493:Leukocyte Common Antigens / Q000032:analysis; D008264:Macrophages / Q000737:chemistry; D053507:Matrix Metalloproteinase 11; D020782:Matrix Metalloproteinases / Q000235:genetics* / Q000378:metabolism; D008666:Metalloendopeptidases; D051379:Mice; D008815:Mice, Inbred Strains; D018345:Mice, Knockout; D009131:Muscle, Smooth, Vascular / Q000201:enzymology / Q000293:injuries / Q000473:pathology; D017539:Tunica Intima / Q000737:chemistry / Q000166:cytology / Q000201:enzymology; D014945:Wound Healing
D000199:Actins; D017493:Leukocyte Common Antigens; D053507:Matrix Metalloproteinase 11; D020782:Matrix Metalloproteinases; D008666:Metalloendopeptidases