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

Background-alpha (v)beta (3)-Integrin receptors are upregulated in atherosc lerotic arteries and play a key role in smooth muscle cell and possibly inf lammatory cell migration. We hypothesized that after balloon angioplasty (B A) 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 under went 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 4 0% 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 sh ow a 50% reduction in macrophage cell density in the XT199 group (716 +/- 4 52 versus 1458 +/- 389 cells/mm(2), P<0.006), Neovessel density at 28 days was also reduced (23<plus/minus>42, versus 58 +/- 46 vessel cross sections/ mm(2), P<0.02), Early after BA tie, 3 to 7 days), there was a decrease in i ntracellular adhesion molecule-1 and vascular cell adhesion molecule-1 expr ession, indicative of a reduction in vascular cell activation. Conclusions-Selective <alpha>(v)beta (3)-receptor blockade for 14 days afte r BA in the focally atherosclerotic rabbit significantly reduced restenosis and limited macrophage infiltration and neovascularization in the vessel w all.