In Vivo Vascular Engineering of Vein Grafts: Directed Migration of Smooth Muscle Cells by Perivascular Release of Elastase Limits Neointimal Proliferation

Abstract

Saphenous vein bypass grafting for coronary revascularization procedures remains limited by accelerated neointima formation. It was hypothesized that creation of a modified chemotactic gradient in vivo could guide migration of smooth muscle cells (SMCs) peripherally instead of in a luminal direction and reduce intimal hyperplasia during vein graft arterialization. Surgical bypass vein grafting to femoral arteries was performed in adult male New Zealand White rabbits (n = 8 per treatment group; five for 7 d and three for 28 d). Controlled-release microspheres delivering elastase or buffered polymer only were administered perivascularly at the vein graft site. At 7 days, five vein grafts per group were harvested and cross-sections were immunostained with anti-proliferating cell nuclear antigen (PCNA) to determine the number and distribution of proliferating SMCs. At 28 days, three vein grafts per group were harvested and intima-to-media (I/M) ratios were calculated after staining with Verhoeff von Gieson-Masson trichrome stain. Significant early outward-directed elastin degradation resulted from elastase treatment. Concurrently, proliferating SMCs migrated peripherally. PCNA(+) cells in the outer half of the wall increased 2.37 fold compared to procedural controls (P <.0001). Directional shifts in SMC migration underlie these results because overall SMC proliferation was not significantly different. At 28 days after vein graft surgery, a 38% reduction (P =.0008) in neointima was observed relative to procedural controls. Directional guidance of SMC responses through perivascular elastase release achieves favorable vein graft remodeling characteristics, including limited neointima development. This represents practical evidence that SMC migration can be directionally guided in vivo in a vein graft model and that plaque progression can be prevented by redistributing elastin without decreasing functional vein graft wall stability.