Rotmans Joris I, Velema Evelyn, Verhagen Hence J M, Blankensteijn Jan D, de Kleijn Dominique P V, Stroes Erik S G, Pasterkamp Gerard
Department of Experimental Cardiology, University Medical Center, Utrecht, The Netherlands.
J Vasc Surg. 2004 Feb;39(2):432-9. doi: 10.1016/j.jvs.2003.07.009.
The patency of arteriovenous (AV) polytetrafluoroethylene grafts for hemodialysis is impaired by intimal hyperplasia (IH) at the venous outflow tract. IH mainly consists of vascular smooth muscle cells, fibroblasts, and extracellular matrix proteins. Because matrix metalloproteinases (MMPs) are enzymes able to degrade extracellular matrix proteins such as elastin and collagen and also stimulate migration of vascular smooth muscle cells, we hypothesized that BB2983 (a broad-spectrum MMP inhibitor) could reduce IH in AV grafts.
In 12 pigs, AV grafts were created bilaterally between the carotid artery and the jugular vein. Six pigs received the oral MMP inhibitor (MMPi), and six pigs served as a control. Four weeks after AV shunting, the grafts and adjacent vessels were excised and underwent histologic analysis. Quantification of elastin content was performed on Elastin von Gieson-stained sections.
At the venous outflow tract, IH was strongly inhibited after MMPi when compared with the control group (1.02 +/- 0.26 mm(2) vs 2.14 +/- 0.38 mm(2); P =.027). The medial area did not differ significantly. In the control group elastin density decreased compared with nonoperated veins. This decrease was not observed in the MMPi group (nonoperated, 6.3% +/- 0.4%; MMPi, 7.2% +/- 0.7% vs untreated, 3.6% +/- 0.5%; P =.0004). Outward remodeling of the vein was not influenced by MMP inhibition.
MMPi reduces IH formation at the venous outflow tract of AV grafts in pigs, probably by inhibiting elastin degradation. These data suggest that MMP inhibitors might be useful for minimizing IH in AV grafts, thus prolonging patency rates of AV grafts in patients on hemodialysis.
动静脉聚四氟乙烯移植物用于血液透析时，其静脉流出道的内膜增生（IH）会损害移植物的通畅性。内膜增生主要由血管平滑肌细胞、成纤维细胞和细胞外基质蛋白组成。由于基质金属蛋白酶（MMPs）是能够降解细胞外基质蛋白（如弹性蛋白和胶原蛋白）并刺激血管平滑肌细胞迁移的酶，我们推测BB2983（一种广谱MMP抑制剂）可以减少动静脉移植物中的内膜增生。
在12头猪身上，双侧在颈动脉和颈静脉之间建立动静脉移植物。6头猪接受口服MMP抑制剂（MMPi），6头猪作为对照。动静脉分流4周后，切除移植物和相邻血管并进行组织学分析。在弹性蛋白冯·吉森染色切片上进行弹性蛋白含量的定量分析。
在静脉流出道，与对照组相比，MMPi治疗后内膜增生受到强烈抑制（1.02±0.26mm²对2.14±0.38mm²；P = 0.027）。中间区域无显著差异。与未手术的静脉相比，对照组弹性蛋白密度降低。在MMPi组中未观察到这种降低（未手术，6.3%±0.4%；MMPi，7.2%±0.7%对未治疗，3.6%±0.5%；P = 0.0004）。静脉的向外重塑不受MMP抑制的影响。
MMPi可能通过抑制弹性蛋白降解减少猪动静脉移植物静脉流出道的内膜增生形成。这些数据表明，MMP抑制剂可能有助于最小化动静脉移植物中的内膜增生，从而延长血液透析患者动静脉移植物的通畅率。
