Enhancement of neointima formation with tissue-type plasminogen activator

Purpose: Indirect evidence suggests that tissue plasminogen activator (tPA) either limits or does not alter restenosis. However, tPA enhances tumor in vasiveness through matrix remodeling, and several elements of degraded matr ix enhance smooth muscle cell mitogenesis. We use either local adenoviral-m ediated overexpression of tPA or systemic infusion of recombinant tPA combi ned with mechanical overdilation of rabbit common femoral arteries to evalu ate the impact of tPA on neointima formation. Methods: Left common femoral arteries of New Zealand white rabbits were tra nsfected in situ either with an adenoviral-construct-expressing tPA or a vi ral control (adenoviral-construct-expressing beta -galactosidase) or nonvir al (buffer) control after balloon angioplasty injury. At 7 and 28 days, lef t common femoral artery segments were harvested (n = 4 for each group and t ime point). Vessel segments were examined for intimate-media ratio, smooth muscle cell proliferation, extracellular matrix, and inflammatory response. Thrombus formation was evaluated after 3 days (n = 3 for each group). In a second experiment, New Zealand white rabbits (n = 3 per group, per time po int) underwent mechanical dilation followed by buffer treatment or systemic tPA infusion according to a widely clinically used accelerated infusion pr otocol. Treated artery segments were harvested after 7 or 28 days and proce ssed for intima-to-media ratio determination and class-wide histochemical d etermination of collagenous extracellular matrix and collagen content. Results: Both rate and degree of neointima formation increase dramatically with overexpression (250%-461% relative to controls at 7 and 28 days). Subs tantial early matrix degradation is observed in vessels treated with local overexpression of tPA, although no increases in local inflammation or in sm ooth muscle proliferation occur. Late enhancement of smooth muscle prolifer ation emerges, consistent with secondary impact of perturbed matrix compone nts. Systemic infusion of tPA according to clinical protocols also results in early and late enhancement of neointima formation in this model (34%-52% relative to controls at at 7 and 28 days), with significant early collagen ous matrix degradation. Systemic infusion, although significant, did not at tain the degree of neointima formation present with overexpression. Conclusion: With some evidence of dose-dependence, tissue plasminogen activ ator enhances neointima formation after angioplasty in a rabbit model. Earl y matrix degradation precedes change in rates of proliferation and underlie s this effect in spite of several antirestenotic actions including decrease d thrombus and decreased macrophage recruitment in this model.