SELECTIVE ALPHA-V-BETA-3 INTEGRIN BLOCKADE POTENTLY LIMITS NEOINTIMALHYPERPLASIA AND LUMEN STENOSIS FOLLOWING DEEP CORONARY ARTERIAL STENTINJURY - EVIDENCE FOR THE FUNCTIONAL IMPORTANCE OF INTEGRIN ALPHA-V-BETA-3 AND OSTEOPONTIN EXPRESSION DURING NEOINTIMA FORMATION

Lumen loss from vascular restenosis remains a leading cause of chronic revascularization failure, Objective: We hypothesized that cell-matri x adhesion, migration, and differentiation events that underlie resten osis are mediated by alpha v beta 3 integrin-ligand interactions. Meth ods: Using immunohistochemistry and in situ hybridization, we examined the spatial and temporal vessel wall expression of alpha v beta 3 and osteopontin following deep coronary arterial injury. Cell migration a nd adhesion assays were performed to demonstrate the affinity and spec ificity of XJ735 for various vessel wall integrins. The effects of XJ 735 (a selective cyclic Arg-Gly-Asp (RGD) peptidomimetic alpha v beta 3 antagonist) on neointimal hyperplasia and lumen stenosis were tested in a porcine coronary injury model, Normolipemic swine underwent over sized stent injury followed by XJ 735 administration (9 animals, 28 le sions; 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), Resul ts: Maximal alpha v beta 3 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 o bserved at 14, 7 and 28 days respectively. IC50 for XJ 735 alpha v bet a 3-mediated inhibition of human and porcine endothelial cell adhesion , and vascular smooth muscle cell migration, ranged from 0.6 to 4.4 mu M. In contrast, IC50 for porcine or human alpha IIb/beta 3, alpha 4 b eta 1, alpha v beta 5, and alpha 5 beta 1 inhibition exceeded 100 mu M . Steady state XJ 735 plasma levels exceeded 5 mu M Despite slightly h igher injury scores in XJ 735 treated animals, significant reductions in mean neointima area (43% reduction; p = 0.0009), and mean percent l umen stenosis (similar to 2.9 fold reduction; p = 0.04) were observed in XJ 735 treated animals, XJ 735 treatment did not significantly alte r the relative size of the arterial injury and reference sites (geomet ric remodeling), Comparison of neontima area vs. injury score regressi on lines revealed significant reductions in slope (p = 0.0001) and int ercept (p = 0.0001) for XJ 735. Conclusions: Selective alpha v beta 3 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 alpha v beta 3 ex pression following vessel wall injury, and the high affinity and speci ficity of XJ 735 for alpha v beta 3, confirms the importance of this i ntegrin in adhesive and migratory cell-matrix events underlying corona ry restenosis. (C) 1997 Elsevier Science B.V.