Xie Yangzhouyun, Zhang Weichang, Thaxton Carly, Jin Ying, Yatsula Bogdan, Bai Hualong, Davis Sean, Exsted Tobias, Dardik Alan, Guzman Raul J, Cai Yujun
Division of Vascular Surgery and Endovascular Therapy, Department of Surgery, Yale School of Medicine, New Haven, CT 06510.
Vascular Biology and Therapeutics Program, Yale School of Medicine, New Haven, CT 06520.
bioRxiv. 2025 Aug 30:2025.08.27.672378. doi: 10.1101/2025.08.27.672378.
OBJECTIVE-: Surgically created upper extremity arteriovenous fistulae (AVF) are the preferred vascular access for patients requiring dialysis. It is estimated, however, that 50% of AVF fail within one year due to aggressive neointimal hyperplasia, which significantly increases morbidity and mortality. Matrix metalloproteinase-3 (MMP-3), also known as stromelysin-1, is a member of the metalloproteinase family that plays a critical role in the pathogenesis of many human disorders by degrading extracellular matrix and regulating molecular signaling pathways. The role of MMP-3 in AVF neointimal failure has not been explored.
APPROACH AND RESULTS-: We observed that MMP-3 was induced in a time-dependent fashion by fetal bovine serum (FBS) and the growth factor PDGF-BB in cultured venous SMC. MMP-3 was also highly expressed in the neointimal SMCs of the outflow veins and the juxta-anastomotic area in an AVF mouse model, as well as in human AVF specimens. Knockdown of MMP-3 significantly suppressed venous SMC proliferation, whereas overexpression of MMP-3 facilitated cell growth . Importantly, deficiency of global and SMC-specific MMP-3 significantly reduced neointimal hyperplasia and improved patency after AVF creation. Mechanistic studies showed that MMP-3-mediated SMC proliferation and AVF neointimal hyperplasia were regulated via the FAK-AKT signaling pathway.
CONCLUSIONS-: These data suggest that MMP-3 is a key mediator of AVF neointimal failure. Targeting local MMP-3 activity may be a novel therapeutic strategy to prevent AVF neointimal failure and improve outcomes in patients requiring hemodialysis.
手术创建的上肢动静脉内瘘（AVF）是需要透析的患者首选的血管通路。然而，据估计，由于侵袭性内膜增生，50%的AVF在一年内失败，这显著增加了发病率和死亡率。基质金属蛋白酶-3（MMP-3），也称为基质溶解素-1，是金属蛋白酶家族的成员，通过降解细胞外基质和调节分子信号通路，在许多人类疾病的发病机制中起关键作用。MMP-3在AVF内膜失败中的作用尚未得到探索。
我们观察到，在培养的静脉平滑肌细胞中，胎牛血清（FBS）和生长因子血小板衍生生长因子-BB（PDGF-BB）以时间依赖性方式诱导MMP-3表达。在AVF小鼠模型的流出静脉和吻合口周围区域的内膜平滑肌细胞以及人类AVF标本中，MMP-3也高度表达。敲低MMP-3显著抑制静脉平滑肌细胞增殖，而MMP-3的过表达促进细胞生长。重要的是，全身性和平滑肌细胞特异性MMP-3的缺乏显著减少了内膜增生，并改善了AVF创建后的通畅性。机制研究表明，MMP-3介导的平滑肌细胞增殖和AVF内膜增生是通过黏着斑激酶-蛋白激酶B（FAK-AKT）信号通路调节的。
这些数据表明，MMP-3是AVF内膜失败的关键介质。靶向局部MMP-3活性可能是一种新的治疗策略，以预防AVF内膜失败并改善需要血液透析的患者的预后。
