Flow-induced neointimal regression in baboon polytetrafluoroethylene grafts is associated with decreased cell proliferation and increased apoptosis
Flow-induced neointimal regression in baboon polytetrafluoroethylene grafts is associated with decreased cell proliferation and increased apoptosis
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DOI：
10.1067/mva.2002.128295
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发表时间：
2002-12-01
影响因子：
4.3
通讯作者：
Clowes, AW
中科院分区：
文献类型：
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作者：
Berceli, SA;Davies, MG;Clowes, AW
目的：我们以前已经证明，狒狒移植物受到高剪切应力表现出增加管腔面积通过萎缩的新生内膜层。本研究旨在观察大鼠海马回退早期平滑肌细胞（SMC）的生长动力学变化，并探讨一氧化氮（NO）在这一过程中的调控作用。16只狒狒接受了双侧聚四氟乙烯髂动脉移植物植入。在8周内形成新生内膜后，通过一个移植物的血流随着下游动静脉瘘的放置而增加。在第4（n = 6）、7（n = 5）和14（n = 5）天收获移植物，并评估新生内膜横截面积、SMC增殖和凋亡以及巨噬细胞浸润。将高流量移植物与对侧正常流量对照进行比较。11只狒狒进行了相同的实验准备，以评估NO抑制的效果。移植物植入后8周，动物接受初始推注（100 mg/kg），然后连续输注（60 mg/kg/d）N-G-硝基-L-精氨酸甲酯（L-NAME; n = 6）或无活性立体异构体N-G-硝基-D-精氨酸甲酯（n = 5）。移植物收获在7天和评价的实验终点，详细previous.Results：远端瘘的位置导致平均中心线速度和壁面剪切应力增加了3.8倍。在血流操作后的最初14天内采集的移植物显示新生内膜横截面积逐渐减少。这种变化与内皮下SMC增殖减少和新生内膜SMC凋亡增加有关，后者位于移植物附近区域。用L-NAME治疗的动物显示血小板环鸟苷酸单磷酸盐减少20%，血清硝酸盐/亚硝酸盐浓度减少17%。尽管这种抑制NO的产生，没有影响的流量依赖性的变化，在新生内膜面积，细胞增殖，或凋亡中观察到的L-NAME-treated baboons.Conclusion：局部血流动力学环境内愈合假体移植调节新生内膜SMC增殖和凋亡。移植物流量增加导致新生内膜萎缩。
Objective: We have previously shown that baboon grafts subjected to elevated shear stress exhibit an increase in luminal area through atrophy of the neointimal layer. This study was designed to investigate the smooth muscle cell (SMC) growth kinetics during early regression and evaluate the influence of nitric oxide (NO) in the regulation of this process.Methods. Sixteen baboons underwent bilateral polytetrafluorethylene aortoiliac graft placement. After development of a neointima over an 8-week period, blood flow through one graft was increased with placement of a downstream arteriovenous fistula. Grafts were harvested at 4 (n = 6), 7 (n = 5), and 14 (n = 5) days and assessed for neointimal cross-sectional area, SMC proliferation and apoptosis, and macrophage infiltration. High-flow grafts were compared with contralateral normal-flow controls. Eleven baboons underwent an identical experimental preparation to evaluate the effect of NO inhibition. Eight weeks after graft implantation, the animals were treated with an initial bolus (100 mg/kg) followed by continuous infusion (60 mg/kg/d) of either N-G-nitro-L-arginine methyl ester (L-NAME; n = 6) or the inactive stereoisomer N-G-nitro-D-arginine methyl ester (n = 5). Grafts were harvested at 7 days and evaluated with the experimental endpoints, detailed previously.Results: Distal fistula placement resulted in a 3.8-fold increase in mean centerline velocity and wall shear stress. Grafts harvested during the initial 14 days after flow manipulation showed a progressive reduction in neointimal cross-sectional area. This change was associated with a decrease in subendothelial SMC proliferation and an increase in neointimal SMC apoptosis, the latter being in the region adjacent to the graft. Animals treated with L-NAME showed a 20% reduction in platelet cyclic guanosine, monophosphate and a 17% reduction in serum nitrate/nitrite concentrations. Despite this inhibition of NO production, no effect on the flow-dependent changes in neointimal area, cell proliferation, or apoptosis was observed in the L-NAME-treated baboons.Conclusion: The local hemodynamic environment within healing prosthetic grafts modulates neointimal SMC proliferation and apoptosis. An increase in graft flow leads to atrophy of the neointima.