Nugent Helen M, Sjin Robert Tjin Tham, White Desmond, Milton Luther G, Manson Roberto J, Lawson Jeffrey H, Edelman Elazer R
Harvard-MIT Division of Health Sciences and Technology, Massachusetts Institute of Technology, Cambridge, MA, USA.
J Vasc Surg. 2007 Sep;46(3):548-556. doi: 10.1016/j.jvs.2007.04.074.
Vascular access dysfunction is a major problem in hemodialysis patients. Only 50% of arteriovenous grafts (AVGs) will remain patent 1 year after surgery. AVGs frequently develop stenoses and occlusions at the venous anastomoses in the venous outflow tract. Lumen diameter is not only determined by intimal thickening but is also influenced by remodeling of the vessel wall. Vascular remodeling requires degradation and reorganization of the extracellular matrix by the degradation enzymes, matrix metalloproteinases (MMPs). In this study, we aimed to provide further insight into the mechanism of endothelial regulation of vascular remodeling and luminal narrowing in AVGs.
End-to-side carotid artery-jugular vein polytetrafluoroethylene grafts were created in 20 domestic swine. The anastomoses and outflow vein were treated with Gelfoam matrices (Pfizer, New York, NY) containing allogeneic porcine aortic endothelial (PAE, n = 10) cells or control matrices without cells (n = 10), and the biologic responses to PAE implants were investigated 3 and 28 days postoperatively. Angiograms before euthanasia were compared with baseline angiograms. Tissue sections were stained with hematoxylin and eosin, Verhoeff elastin, and antibodies specific to MMP-9 and MMP-2 and underwent histopathologic, morphometric and immunohistochemical analysis.
Veins treated with PAE cell implants had a 2.8-fold increase in venous lumen diameter compared with baseline (P < .05), a 2.3-fold increase in lumen diameter compared with control, and an 81% decrease in stenosis (P < .05) compared with control at 28 days. The increase in lumen diameter by angiographic analysis correlated with morphometric analysis of tissue sections. PAE implants increased the venous lumen area 2.3-fold (P < .05), decreased venous luminal occlusion 66%, and increased positive venous remodeling 1.9-fold (P < .05) compared with control at 28 days. PAE cell implants reduced MMP-2 expression and neovascularization at 3 and 28 days and adventitial fibrosis at 28 days, suggesting a role of the implants in controlling the affects of medial and adventitial cells in the response to vascular injury.
These results demonstrate that the adventitial application of endothelial implants significantly reduced MMP-2 expression within the venous wall, and increased venous lumen diameter and positive remodeling in a porcine arteriovenous graft model. Adventitial endothelial implants may be useful in decreasing luminal narrowing in a clinical setting.
血管通路功能障碍是血液透析患者的一个主要问题。动静脉移植物（AVG）术后1年仅有50%能保持通畅。AVG在静脉流出道的静脉吻合口处常发生狭窄和闭塞。管腔直径不仅由内膜增厚决定，还受血管壁重塑的影响。血管重塑需要降解酶基质金属蛋白酶（MMPs）对细胞外基质进行降解和重组。在本研究中，我们旨在进一步深入了解AVG中血管重塑和管腔狭窄的内皮调节机制。
在20头家猪身上制作端侧颈动脉-颈静脉聚四氟乙烯移植物。将含有同种异体猪主动脉内皮（PAE，n = 10）细胞的明胶海绵基质（辉瑞公司，纽约，NY）或无细胞的对照基质应用于吻合口和流出静脉，术后3天和28天研究对PAE植入物的生物学反应。将安乐死前行血管造影与基线血管造影进行比较。组织切片用苏木精和伊红、Verhoeff弹性蛋白以及MMP-9和MMP-2特异性抗体染色，并进行组织病理学、形态计量学和免疫组织化学分析。
与基线相比，接受PAE细胞植入物处理的静脉管腔直径增加了2.8倍（P < 0.05），与对照相比管腔直径增加了2.3倍，在28天时与对照相比狭窄减少了81%（P < 0.05）。血管造影分析显示的管腔直径增加与组织切片的形态计量学分析相关。与对照相比，PAE植入物在28天时使静脉管腔面积增加了2.3倍（P < 0.05），静脉管腔闭塞减少了66%，静脉正向重塑增加了1.9倍（P < 0.05）。PAE细胞植入物在术后3天和28天时降低了MMP-2表达和新生血管形成，在28天时减少了外膜纤维化，提示植入物在控制血管损伤反应中中膜和外膜细胞的影响方面发挥作用。
这些结果表明，在猪动静脉移植物模型中，外膜应用内皮植入物可显著降低静脉壁内MMP-2表达，并增加静脉管腔直径和正向重塑。外膜内皮植入物在临床环境中可能有助于减少管腔狭窄。
