Misra Sanjay, Doherty Michael G, Woodrum David, Homburger Jay, Mandrekar Jaywant N, Elkouri Stephane, Sabater Enrique A, Bjarnason Haraldur, Fu Alex A, Glockner James F, Greene Eddie L, Mukhopadhyay Debabrata
Department of Radiology, Division of Vascular Surgery, Division of Cardiovascular Diseases and Internal Medicine, Mayo Clinic, Rochester, MN 55905, USA.
Kidney Int. 2005 Dec;68(6):2890-900. doi: 10.1111/j.1523-1755.2005.00763.x.
We hypothesized the source of early proliferating cells contributing to venous stenosis formation in a porcine hemodialysis grafts is the adventitia and media, and migration of these cells is greatest within the first two weeks following graft placement, resulting in increased matrix metalloproteinase-2 (MMP-2) activity.
Polytetrafluoroethylene grafts from the iliac artery to the ipsilateral iliac vein were placed in 23 pigs and 5-Bromo-2'-deoxyuridine (BrdU) was given at 24 and 48 hours after surgery to assess cell proliferation and migration. Angiography and magnetic resonance angiography was performed. Animals were euthanized on day three (N= 6), day seven, (N= 5), day 14 (N= 6), and days 19 to 26 (N= 6) after graft placement, and stenotic tissue and unaffected contralateral iliac vein were removed for zymography and immunostaining.
Migration of cells derived from the adventitia and media peaked at day 14. Adventitial diameter of the stenotic vein decreased, while the intima to media ratio increased. MMP-2 activity peaks at day seven in the adventitia and days 19 to 26 in the intima.
These results confirm our hypothesis that the source of cells resulting in venous stenosis formation is derived from the adventitia and media, with cell migration being greatest within the first two weeks after graft placement with translocation of these cells into the intima at four weeks. MMP-2 activity peaks at day seven in the adventitia and again at days 19 to 26 in the intima. A key to limiting venous stenosis formation may lie in inhibiting MMP-2 by adventitial and medial targeting.
我们推测，在猪血液透析移植物中，导致静脉狭窄形成的早期增殖细胞来源是外膜和中膜，并且这些细胞的迁移在移植物植入后的头两周内最为显著，从而导致基质金属蛋白酶-2（MMP-2）活性增加。
将从髂动脉到同侧髂静脉的聚四氟乙烯移植物植入23头猪体内，并在术后24小时和48小时给予5-溴-2'-脱氧尿苷（BrdU），以评估细胞增殖和迁移情况。进行血管造影和磁共振血管造影。在移植物植入后的第3天（n = 6）、第7天（n = 5）、第14天（n = 6）以及第19至26天（n = 6）对动物实施安乐死，并切除狭窄组织和未受影响的对侧髂静脉，用于酶谱分析和免疫染色。
来自外膜和中膜的细胞迁移在第14天达到峰值。狭窄静脉的外膜直径减小，而内膜与中膜的比例增加。MMP-2活性在外膜中于第7天达到峰值，在内膜中于第19至26天达到峰值。
这些结果证实了我们的假设，即导致静脉狭窄形成的细胞来源是外膜和中膜，细胞迁移在移植物植入后的头两周内最为显著，这些细胞在四周时转移至内膜。MMP-2活性在外膜中于第7天达到峰值，在内膜中于第19至26天再次达到峰值。限制静脉狭窄形成的一个关键可能在于通过靶向外膜和中膜来抑制MMP-2。
