Directed migration of smooth muscle cells to engineer plaque-resistant vein grafts

Purpose: To test the hypothesis that controlled perivascular release of tissue plasminogen activator (tPA) can generate cleaved extracellular matrix (ECM) chemotactic gradients to guide the migration of vascular smooth muscle cells (SMCs) away from the lumen, thereby limiting neointima formation. Methods: This hypothesis was tested in rabbit models in which the perivascular surface of vein bypass grafts was treated with microspheres releasing tPA (MS-tPA), microspheres containing no drug (MS-blank), or phosphate buffered saline (PBS). Vein graft segments harvested after 7 days were then evaluated for elastin content, proliferating SMCs, intima-to-media (I/M) ratio, and inflammation; late impact on neointima formation was also examined. Results: The 7-day results demonstrated cleaved elastin gradients and proliferating SMCs that assumed a more peripheral distribution in the MS-tPA group than MS-blank and PBS controls (p < 0.05). At 28 days, vein grafts treated with MS-tPA showed a mean IN ratio (0.35 +/- 0.04) that was 63.5% lower than PBS controls (0.96 +/- 0.07, p < 0.005) and 43.5% lower than MS-blank specimens (0.62 +/- 0.08, p < 0.05). Conclusions: Perivascular release of tPA modifies ECM gradients, directionally guides SMC migration away from the lumen, and limits neointima formation.