Selective αvβ3-receptor blockade reduces macrophage infiltration and restenosis after balloon angioplasty in the atherosclerotic rabbit

Abstract

Background - αvβ3-Integrin receptors are upregulated in atherosclerotic arteries and play a key role in smooth muscle cell and possibly inflammatory cell migration. We hypothesized that after balloon angioplasty (BA) of atherosclerotic arteries, selective inhibition of the αvβ3-receptor by XT199, a small-molecule, non-peptide-selective αvβ3-receptor antagonist, would reduce restenosis. Methods and Results - After induction of focal atherosclerosis, rabbits underwent femoral BA and received XT199 (2.5 mg/kg IV bolus plus 2.5 mg · kg-1 · d-1 IV; n= 19) or vehicle (n=20) for 14 days. At 28 days after BA, the XT199 group had a larger lumen (0.75±0.26 versus 0.57±0.20 mm2, P=0.03) and a smaller neointimal area (0.49±0.18 versus 0.68±0.25 mm2, P = 0.01) than the vehicle group. Angiographic analysis confirmed a 30% to 40% reduction in restenosis. Arteries harvested at 28 days after BA did not show a reduction in intima plus media smooth muscle cell content but did show a 50% reduction in macrophage cell density in the XT199 group (716±452 versus 1458±989 cells/mm2, P<0.006). Neovessel density at 28 days was also reduced (23±42 versus 58±46 vessel cross sections/mm2, P<0.02). Early after BA (ie, 3 to 7 days), there was a decrease in intracellular adhesion molecule-1 and vascular cell adhesion molecule-1 expression, indicative of a reduction in vascular cell activation. Conclusions - Selective αvβ3-receptor blockade for 14 days after BA in the focally atherosclerotic rabbit significantly reduced restenosis and limited macrophage infiltration and neovascularization in the vessel wall.