© 1997 by European Society of Cardiology
Copyright © 1997, European Society of Cardiology
Selective 
vβ3 integrin blockade potently limits neointimal hyperplasia and lumen stenosis following deep coronary arterial stent injury1:
Evidence for the functional importance of integrin 
vβ3 and osteopontin expression during neointima formation
aDivision of Cardiology, Department of Internal Medicine, Mayo Clinic and Mayo Foundation, Rochester, MN 55905, USA
bDivision of Endocrinology and Metabolism, Department of Internal Medicine, Mayo Clinic and Mayo Foundation, Rochester, MN 55905, USA
cDuPont Merck Pharmaceutical Company, Route 141 & Henry Clay Road, Experimental Station, Wilmington, DE 19880-0400, USA
* Corresponding author. Tel: +1 (302) 695 8418; E-mail: mousasa@a1.lldmpc.umc.dupont.com
Lumen loss from vascular restenosis remains a leading cause of chronic revascularization failure. Objective: We hypothesized that cell-matrix adhesion, migration, and differentiation events that underlie restenosis are mediated by vβ3 integrin-ligand interactions. Methods: Using immunohistochemistry and in situ hybridization, we examined the spatial and temporal vessel wall expression of vβ3 and osteopontin following deep coronary arterial injury. Cell migration and adhesion assays were performed to demonstrate the affinity and specificity of XJ735 for various vessel wall integrins. The effects of XJ 735 (a selective cyclic Arg-Gly-Asp (RGD) peptidomimetic vβ3 antagonist) on neointimal hyperplasia and lumen stenosis were tested in a porcine coronary injury model. Normolipemic swine underwent oversized stent injury followed by XJ 735 administration (9 animals, 28 lesions; 1 mg/kg bolus+7 days 4 mg/kg/d infusion+21 days 2 mg/kg i.v. bolus 12 hourly) or placebo (10 animals, 30 arterial lesions). Results: Maximal vβ3 immunoreactivity was observed between 7–14 days following injury in the neointima, media, and adventitia. Maximal osteopontin mRNA signal in the neointima, media, and adventitia was observed at 14, 7 and 28 days respectively. IC50 for XJ 735 vβ3-mediated inhibition of human and porcine endothelial cell adhesion, and vascular smooth muscle cell migration, ranged from 0.6 to 4.4 µM. In contrast, IC50 for porcine or human IIb/β3, 4β1, vβ5, and 5β1 inhibition exceeded 100 µM. Steady state XJ 735 plasma levels exceeded 5 µM. Despite slightly higher injury scores in XJ 735 treated animals, significant reductions in mean neointima area (43% reduction; p = 0.0009), and mean percent lumen stenosis (
2.9 fold reduction; p = 0.04) were observed in XJ 735 treated animals. XJ 735 treatment did not significantly alter the relative size of the arterial injury and reference sites (geometric remodeling). Comparison of neontima area vs. injury score regression lines revealed significant reductions in slope (p = 0.0001) and intercept (p = 0.0001) for XJ 735. Conclusions: Selective vβ3 blockade is an effective anti-restenosis strategy that potently limits neointimal growth and lumen stenosis following deep arterial injury. The co-ordinate spatial and temporal upregulation of vβ3 expression following vessel wall injury, and the high affinity and specificity of XJ 735 for vβ3, confirms the importance of this integrin in adhesive and migratory cell-matrix events underlying coronary restenosis.
KEYWORDS Alpha v beta 3; Porcine coronary; Stent; Adhesion; Migration; Restenosis; Remodeling; Integrins
1 This work was presented in part at the 69th Scientific Sessions of the American Heart Association, New Orleans, Louisiana, November 1996.
2 Present address: Tanabe Seiyaku Co., Saitama, Japan.
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