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 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.


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.
Bishop
G G
GG
University of Virginia, Charlottesville, VA, USA.
McPherson
J A
JA
Sanders
J M
JM
Hesselbacher
S E
SE
Feldman
M J
MJ
McNamara
C A
CA
Gimple
L W
LW
Powers
E R
ER
Mousa
S A
SA
Sarembock
I J
IJ
D000199:Actins / Q000032:analysis; D000800:Angioplasty, Balloon; D000818:Animals; D001157:Arterial Occlusive Diseases / Q000473:pathology / Q000517:prevention & control*; D001161:Arteriosclerosis / Q000473:pathology / Q000628:therapy*; D002448:Cell Adhesion / Q000187:drug effects; D002478:Cells, Cultured; D018932:Chemokine CCL2 / Q000378:metabolism; D002784:Cholesterol / Q000097:blood; D004305:Dose-Response Relationship, Drug; D005263:Femoral Artery / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D007093:Imidazoles / Q000494:pharmacology; D007150:Immunohistochemistry; D018799:Intercellular Adhesion Molecule-1 / Q000187:drug effects / Q000378:metabolism; D008264:Macrophages / Q000187:drug effects* / Q000473:pathology; D008297:Male; D009131:Muscle, Smooth, Vascular / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D011817:Rabbits; D019030:Receptors, Vitronectin / Q000037:antagonists & inhibitors* / Q000378:metabolism; D012008:Recurrence; D013997:Time Factors; D017539:Tunica Intima / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D017540:Tunica Media / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D019010:Vascular Cell Adhesion Molecule-1 / Q000187:drug effects / Q000378:metabolism
C426703:3-(3-(3-(4,5-dihydroimidazol-2-ylamino)propyloxylisoxazol-5-yl)carbonylamino)-2-(phenylsulfonylamino)propionic acid; D000199:Actins; D018932:Chemokine CCL2; D007093:Imidazoles; D019030:Receptors, Vitronectin; D019010:Vascular Cell Adhesion Molecule-1; D018799:Intercellular Adhesion Molecule-1; D002784:Cholesterol