Remodeling of the vessel wall after balloon angioplasty injury is incompletely understood, and in particular, the role of extracellular matrix synthesis in restenosis has received little attention. The objective of the present study was to determine the sequence of changes in collagen, elastin, and proteoglycan synthesis and content after balloon injury and to relate these changes to growth of the intimal lesions and extent of cell proliferation. In a double-injury non-cholesterol-fed model, right iliac arterial lesions in 43 rabbits were treated with balloon angioplasty, and the rabbits were killed at five time points ranging from immediate to 12 weeks. Vessel wall collagen and elastin content and synthesis were measured after incubation with '4C-proline and separation with a cyanogen bromide extraction procedure. assess cell proliferation. The intimal area significantly increased from 0.27±0.08 to 0.73±0.11 mm2 between 0 and 12 weeks. Intimal and medial cell proliferation were modest and peaked at 1 week (labeling indexes of 4.8% and 3.0%, respectively) and then markedly declined by 2 weeks. Significant increases in collagen, elastin, and proteoglycan synthesis, up to 4 to 10 times above control nondamaged contralateral iliac arteries, were noted at 1, 2, and 4 weeks. These increases in synthesis were accompanied by significant increases in collagen and elastin content (by "=35%) that coincided with the temporal increase in cross-sectional area. Our data suggest that extracellular matrix formation is a major factor in the development of the restenosis lesion. (Circ Res. 1994;75: 650-658.)

Extracellular matrix formation is the major component of the restenosis lesion that develops after balloon angioplasty. Although ex vivo studies have shown that the synthesis of collagen is stimulated early after balloon angioplasty, there is a delay in accumulation in the vessel wall. The objectives of this study were to assess collagen turnover and its possible regulation by matrix metalloproteinases (MMPs) in a double-injury iliac artery rabbit model of restenosis. Rabbits were killed at four time points (immediately and at 1, 4, and 12 weeks) after balloon angioplasty. In vivo collagen synthesis and collagen degradation were measured after a 24-hour incubation with [14C]proline. Arterial extracts were also run on gelatin zymograms to determine MMP (gelatinase) activity. Collagen turnover studies were repeated in a group of 1-week postangioplasty rabbits that were treated with daily subcutaneous injections of either a nonspecific MMP inhibitor, GM6001 (100 mg/kg per day), or placebo. Collagen synthesis and degradation showed similar temporal profiles, with significant increases in the balloon-injured iliac arteries compared with control nondilated contralateral iliac arteries immediately after angioplasty and at 1 and 4 weeks. Peak collagen synthesis and degradation occurred at 1 week and were increased (approximately four and three times control values, respectively). Gelatin zymography was consistent with the biochemical data by showing an increase of a 72-kD gelatinase (MMP-2) in the balloon-injured side immediately after the second injury, peaking at 1 week, and still detectable at 4 and 12 weeks (although at lower levels). In balloon-injured arteries, the MMP inhibitor reduced both collagen synthesis and degradation. Overall, at 1 week after balloon angioplasty, GM6001 resulted in a 33% reduction in collagen content in balloon-injured arteries compared with placebo (750 +/- 143 to 500 +/- 78 micrograms hydroxyproline per segment, P < .004), which was associated with a nonsignificant 25% reduction in intimal area. Our data suggest that degradation of newly synthesized collagen is an important mechanism regulating collagen accumulation and that MMPs have an integral role in collagen turnover after balloon angioplasty.

An investigation of the relative importance of bandage design, experience of bandager and size of limb on sub-bandage pressures.