Selective alpha(v)beta(3)-receptor blockade reduces macrophage infiltration and restenosis after balloon angioplasty in the atherosclerotic rabbit

Abstract

Background: alpha(v)beta(3)-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 alpha(v)beta(3)-receptor by XT199, a small-molecule, non-peptide-selective alpha(v)beta(3)-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 mm(2), P=0.03) and a smaller neointimal area (0.49+/-0.18 versus 0.68+/-0.25 mm(2), 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/mm(2), P<0.006). Neovessel density at 28 days was also reduced (23+/-42 versus 58+/-46 vessel cross sections/mm(2), 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 alpha(v)beta(3)-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.