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      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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          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.

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          Most cited references 4

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          Vascular endothelial cell proliferation in culture and the influence of flow.

           M. Levesque (1990)
          The influence of laminar shear stress on cell proliferation was investigated for subconfluent bovine aortic endothelial cell monolayers seeded on either glass or Thermanox. The effect of both steady and pulsatile shear stress was studied. For bovine aortic endothelial cells on Thermanox exposed to steady flow, shear stress levels greater than 15 dyne/cm2 resulted in a dose-related reduction in the rate of cell proliferation. At 90 dyne/cm2, the rate of proliferation was virtually totally arrested for 48 h, but then resumed. Pulsatile shear stress produced an exaggeration of the effect observed in response to steady shear stress. Bovine aortic endothelial cells seeded on glass, exhibited a similar but more sensitive response, with a significant reduction in growth rate observed after 24 h at shear stress levels greater than 5 dyne/cm2 and a near cessation of proliferation at 13 dyne/cm2.
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            Blood flow and kinetics of smooth muscle cell proliferation in canine autogenous vein grafts: in vivo BrdU incorporation.

            The effects of blood flow on the kinetics of smooth muscle cell (SMC) proliferation were examined in canine autogenous vein grafts with a distal poor run-off model. The in vivo bromodeoxyuridine (BrdU, a thymidine analogue) incorporation method was used to label proliferating SMCs in each layer of the vein graft. The BrdU labeling index (LI) was defined as a percentage of labeled cells compared to the total number of SMCs, and BrdU LIs were measured in the media and the intima of the graft. The development of intimal thickening of grafts was accelerated at 2 to 4 weeks after implantation. In poor run-off limbs with an abnormal blood flow condition, as characterized by a low flow and a low shear stress variation, the intima of the graft thickened more progressively than that in control limbs with a normal blood flow. In both groups, the medial BrdU LIs reached a maximum 3 to 5 days after implantation and decreased thereafter. The peak of the intimal BrdU LIs occurred at 1 week in both groups. The intimal LIs of the grafts in poor run-off limbs (6.34% at 1 week and 2.97% at 2 weeks) were significantly higher than those in control limbs (5.34 and 1.98%) for 2 weeks after implantation (P < 0.05). The medial SMC proliferation and the following intimal SMC proliferation of vein grafts were accelerated prior to development of the intimal thickening. SMC proliferation in the intima was prominent in a poor run-off limb with a low flow and a low shear stress variation.
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              The characteristics and anatomic distribution of lesions that cause reversed vein graft failure: A five-year prospective study


                Author and article information

                J Vasc Res
                Journal of Vascular Research
                S. Karger AG
                December 2000
                10 January 2001
                : 37
                : 6
                : 576-584
                Departments of aSurgery and bPhysiology and Biophysics, Mayo Clinic and Foundation, Rochester, Minn., USA
                54091 J Vasc Res 2000;37:576–584
                © 2000 S. Karger AG, Basel

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                Page count
                Figures: 6, References: 28, Pages: 9
                Research Paper


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