Early Remodeling of Saphenous Vein Grafts: Proliferation, Migration and Apoptosis of Adventitial and Medial Cells Occur Simultaneously with Changes in Graft Diameter and Blood Flow

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Abstract
Background: This study was designed to determine how migration and proliferation of adventitial and medial cells correlate temporally with hemodynamic characteristics including changes in diameter and blood flow in vein grafts. Methods: Male mongrel dogs underwent end-to-side reversed saphenous vein bypass grafting across a ligated femoral artery. Hemodynamic parameters were assessed by duplex ultrasound. Proliferating cells were labeled 24–48 h after grafting with 5-bromo-2′-deoxyuridine (BrdU). Grafts were removed on postoperative days 2, 5, 7 and 14. Immunohistochemistry was performed on graft sections with antibodies to nuclear antigen Ki-67 (MIB-1), BrdU and smooth muscle cell markers. Apoptosis was identified by modified TUNEL staining. Proliferating/apoptotic cells were quantified digitally. Results: Mean luminal cross-sectional area, blood flow and velocity increased from day 2 to 7. Cell proliferation was evident in adventitia and media on day 2, maximum on day 5 and decreased significantly by day 14. Apoptosis was maximum on day 5. Early proliferating cells (BrdU labeled) localized in the adventitia and media on day 2 were more prevalent in the neointima on days 5–14 suggesting inward migration. On day 2, proliferating cells stained positive only for vimentin. By days 5–14, proliferating cells stained for α-smooth-muscle actin, a phenotype characteristic of myofibroblasts. Conclusion: These results indicate that cell proliferation and apoptosis occur simultaneously within the adventitia and media of the vein during the first week following grafting, when changes in diameter and blood flow are greatest. In addition, proliferating adventitial cells subsequently migrate inwards to contribute to the formation of neointima.