Selective alpha v beta 3 integrin blockade potently limits neointimal hyperplasia and lumen stenosis following deep coronary arterial stent injury: evidence for the functional importance of integrin alpha v beta 3 and osteopontin expression during neointima formation

Cardiovascular Research
S S SrivatsaS A Mousa

Abstract

Lumen loss from vascular restenosis remains a leading cause of chronic revascularization failure. We hypothesized that cell-matrix adhesion, migration, and differentiation events that underlie restenosis are mediated by alpha v beta 3 integrin-ligand interactions. 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 and adhesion assays were performed to demonstrate the affinity and specificity of XJ 735 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 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). 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 observed at 14, ...Continue Reading

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