Effect of selective or combined inhibition of integrins αIIbβ3 and αvβ3 thrombosis and neointima after oversized porcine coronary angioplasty

Abstract

Background - Thrombosis and neointima formation limit the efficacy of coronary angioplasty (PTCA). Clinical trials have implicated the adhesion molecules integrin αIIbβ3 and integrin αvβ3 in these processes. The roles of these molecules in vascular smooth muscle cell adhesion, platelet aggregation, and the thrombotic and neointimal response to oversize porcine PTCA was investigated by use of a selective αIIbβ3 antagonist (lamifiban), a selective αvβ3 antagonist (VO514), and a combined αIIbβ3/αvβ3 antagonist (G3580). Methods and Results - In vitro, both αvβ3 inhibitors caused dose-dependent inhibition of porcine vascular smooth muscle cell adhesion to vitronectin but not to collagen type IV, fibronectin, or laminin, whereas selective αIIbβ3 inhibition had no effect. Intravenous infusions of either αIIbβ3 inhibitor in swine profoundly inhibited ex vivo platelet aggregation to ADP, whereas selective αvβ3 inhibition had no effect. In a porcine PTCA model, intravenous infusions of the integrin antagonists were administered for 14 days after oversized balloon angioplasty injury. After PTCA, there was regional upregulation of integrin αvβ3 in the developing neointima, as assessed by immunohistochemistry. Six hours after PTCA, obstruction of lumen by thrombus was reduced significantly by αIIbβ3 inhibition compared with either control or αvβ3 inhibition (mean control, 18.7%; VO514, 18.5%; lamifiban, 6.4%; G3580, 7.9%). Twenty-eight days after PTCA, there was a significant reduction of neointima with inhibitors of either integrin (mean intima/media ratio: control, 3.08; VO514, 1.33; lamifiban, 0.97; G3580, 1.32). Conclusions - We conclude that both integrin αIIbβ3 and integrin αvβ3 participate in neointima development after experimental angioplasty.