A potential physiological role of stromelysin-1 (MMP-8) in the express
ion or activation of gelatinase A (MMP-2) or gelatinase B (MMP-9) in t
he wall of injured arteries was studied with the use of homozygous MMP
-8-deficient (MMP3(-/-)) mice. One week after perivascular electric in
jury 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, Acti
ve 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, wher
eas one week after injury its contribution to the total MMP-9 level wa
s 11% to 18% for MMP-3(+/+) and MMP-3(-/-) mice. Immunostaining of art
erial sections confirmed enhanced expression of both MMP-2 and MMP-9 a
fter vascular injury. Double immunostaining showed colocalization of M
MP-9 with macrophages in the adventitia, whereas MMP-2 was also detect
ed mainly in the adventitia but failed to colocalize with smooth muscl
e cells. Cell culture experiments confirmed comparable ratios of activ
e versus latent MMP-2 in skin fibroblasts and smooth muscle cells deri
ved from MMP-3(+/+) and MMP-3(-/-) mice. Addition of plasmin(ogen) did
not significantly affect activation of proMMP-2, In MMP-3(+/+) and MM
P-3(-/-) macrophages, comparable levels of 94 kD proMMP-9 were detecte
d, 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. (C)
1998 by The American Society of Hematology.