IN-VIVO COLLAGEN TURNOVER FOLLOWING EXPERIMENTAL BALLOON ANGIOPLASTY INJURY AND THE ROLE OF MATRIX METALLOPROTEINASES

Extracellular matrix formation is the major component of the restenosi s lesion that develops after balloon angioplasty. Although ex vivo stu dies have shown that the synthesis of collagen is stimulated early aft er balloon angioplasty, there is a delay in accumulation in the vessel wall. The objectives of this study were to assess collagen turnover a nd its possible regulation by matrix metalloproteinases (MMPs) in a do uble-injury iliac artery rabbit model of restenosis. Rabbits were kill ed at four time points (immediately and at 1, 4, and 12 weeks) after b alloon angioplasty. in vivo collagen synthesis and collagen degradatio n were measured after a 24-hour incubation with [C-14]proline. Arteria l extracts were also run on gelatin zymograms to determine MMP (gelati nase) activity. Collagen turnover studies were repeated in a group of 1-week postangioplasty rabbits that were treated with daily subcutaneo us injections of either a nonspecific MMP inhibitor, GM6001 (100 mg/kg per day), or placebo. Collagen synthesis and degradation showed simil ar temporal profiles, with significant increases in the balloon-injure d iliac arteries compared with control nondilated contralateral iliac arteries immediately after angioplasty and at 1 and 4 weeks. Peak coll agen synthesis and degradation occurred at 1 week and were increased ( approximately four and three times control values, respectively). Gela tin zymography was consistent with the biochemical data by showing an increase of a 72-kD gelatinase (MMP-2) in the balloon-injured side imm ediately after the second injury, peaking at 1 week, and still detecta ble at 4 and 12 weeks (although at lower levels). In balloon-injured a rteries, the MMP inhibitor reduced both collagen synthesis and degrada tion. Overall, at I week after balloon angioplasty, GM6001 resulted in a 33% reduction in collagen content in balloon-injured arteries compa red with placebo (750+/-143 to 509+/-78 mu g hydroxyproline per segmen t, P<.004), which was associated with a nonsignificant 25% reduction i n intimal area. Our data suggest that degradation of newly synthesized collagen is an important mechanism regulating collagen accumulation a nd that MMPs have an integral role in collagen turnover after balloon angioplasty.