title: Stromelysin-1 (MMP-3)-independent gelatinase expression and activation in mice.
abstract: A potential physiological role of stromelysin-1 (MMP-3) in the expression or activation of gelatinase A (MMP-2) or gelatinase B (MMP-9) in the wall of injured arteries was studied with the use of homozygous MMP-3-deficient (MMP-3-/-) mice. One week after perivascular electric injury of the carotid or femoral artery in wild-type (MMP-3+/+) or MMP-3-/- mice, 70 kD and 65 kD proMMP-2 levels were enhanced by twofold to fourfold, with corresponding increases of 20- to 40-fold for active 61 kD and 58 kD MMP-2, and of 10- to 80-fold for 94 kD proMMP-9. Active MMP-2 species represented approximately one third of the total MMP-2 concentration for both MMP-3+/+ and MMP-3-/- mice. Active 83 kD MMP-9 was not detected in noninjured carotid or femoral arteries, whereas one week after injury its contribution to the total MMP-9 level was 11% to 18% for MMP-3+/+ and MMP-3-/- mice. Immunostaining of arterial sections confirmed enhanced expression of both MMP-2 and MMP-9 after vascular injury. Double immunostaining showed colocalization of MMP-9 with macrophages in the adventitia, whereas MMP-2 was also detected mainly in the adventitia but failed to colocalize with smooth muscle cells. Cell culture experiments confirmed comparable ratios of active versus latent MMP-2 in skin fibroblasts and smooth muscle cells derived from MMP-3+/+ and MMP-3-/- mice. Addition of plasmin(ogen) did not significantly affect activation of proMMP-2. In MMP-3+/+ and MMP-3-/- macrophages, comparable levels of 94 kD proMMP-9 were detected, and plasmin(ogen)-mediated conversion to 83 kD MMP-9 was obtained in both genotypes. These data thus indicate that proMMP-2 activation may occur via a plasmin- and MMP-3-independent mechanism, whereas plasmin can directly activate proMMP-9 via a MMP-3-independent mechanism.
authors.affiliation: Center for Molecular and Vascular Biology, University of Leuven, Leuven, Belgium.
authors.forename: H R
authors.initials: HR
authors.lastname: Lijnen
authors.forename: J
authors.initials: J
authors.lastname: Silence
authors.forename: B
authors.initials: B
authors.lastname: Van Hoef
authors.forename: D
authors.initials: D
authors.lastname: Collen
mesh_terms: D000818:Animals; D002339:Carotid Arteries / Q000473:pathology; D020212:Carotid Artery Injuries; D002478:Cells, Cultured; D017364:Collagenases / Q000096:biosynthesis* / Q000235:genetics; D004789:Enzyme Activation; D004790:Enzyme Induction; D004792:Enzyme Precursors / Q000378:metabolism; D005109:Extracellular Matrix / Q000378:metabolism; D005263:Femoral Artery / Q000293:injuries / Q000473:pathology; D005341:Fibrinolysin / Q000502:physiology; D005347:Fibroblasts / Q000201:enzymology; D018093:Gelatinases / Q000096:biosynthesis* / Q000235:genetics; D006579:Heterozygote; D006801:Humans; D017737:Macrophages, Peritoneal / Q000201:enzymology; D020778:Matrix Metalloproteinase 2; D019278:Matrix Metalloproteinase 3 / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D020780:Matrix Metalloproteinase 9; D008666:Metalloendopeptidases / Q000096:biosynthesis* / Q000235:genetics; D051379:Mice; D018345:Mice, Knockout; D009131:Muscle, Smooth, Vascular / Q000201:enzymology; D014945:Wound Healing / Q000502:physiology*
chemical_list: D004792:Enzyme Precursors; D005341:Fibrinolysin; D017364:Collagenases; D018093:Gelatinases; D008666:Metalloendopeptidases; D019278:Matrix Metalloproteinase 3; D020778:Matrix Metalloproteinase 2; D020780:Matrix Metalloproteinase 9