A Novel v 3 Integrin Antagonist Suppresses Neointima Formation for More Than 4 Weeks After Balloon Injury in Rats

Objectives—We performed a detailed kinetic analysis in a rat balloon injury model to clarify the essential roles of v 3 integrin and endothelial cell (EC) regeneration in neointima formation. Using this model, we evaluated the antistenotic effect of Dainippon compound BS-1417, a novel v 3 integrin antagonist. Methods and Results—Kinetic analysis using RT-PCR showed that v 3 integrin-related genes are upregulated before neointima formation. Morphological and functional analyses revealed that EC regeneration requires 4 weeks after injury, and that recovery of EC normal function coincides with the arrest of neointima formation. Subcutaneous infusion of BS-1417 for 2, 4, 7, or 12 weeks after injury potently inhibited neointima formation without affecting EC regeneration. Although withdrawal of treatment with BS-1417 after short-term administration after injury resulted in catch-up growth of neointima, a long-term study suggested that this catch-up growth can be prevented by continuous administration of BS-1417 until EC regeneration. Conclusion—We clarified that v 3 integrin and EC regeneration play an essential role in neointima formation, and that continuous administration of BS-1417 potently and stably inhibits neointima formation without affecting EC regeneration. These findings suggest that BS-1417 might be useful as a novel systemic drug for the treatment of restenosis. (Arterioscler Thromb Vasc Biol. 2005;25:1376-1382.)