Gonzalez Luis A, Zhang Weichang, Bai Hualong, Taniguchi Ryosuke, Ramachandra Abhay B, Jovin Daniel G, Ohashi Yuichi, Nguyen Mytien, Thaxton Carly, Yatsula Bogdan, Vazquez-Padron Roberto I, Humphrey Jay D, Martin Kathleen A, Kyriakides Themis R, Dardik Alan
Yale School of Medicine, New Haven, Connecticut, United States.
Vascular Biology and Therapeutics Program, Yale School of Medicine, New Haven, Connecticut, United States.
Am J Physiol Heart Circ Physiol. 2025 Jun 1;328(6):H1147-H1167. doi: 10.1152/ajpheart.00661.2024. Epub 2025 Apr 17.
End-stage kidney disease (ESKD) impacts over 740,000 individuals in the United States, with many patients relying on arteriovenous fistulae (AVF) for hemodialysis due to superior patency and reduced infections. However, AVF patency is reduced by thrombosis and neointimal hyperplasia, yielding a 1-yr patency of only 40%-50%. We hypothesized that tenascin-C (TNC), a regulator of inflammation and immune responses after injury, also regulates venous remodeling during AVF maturation. AVF were created in wild-type (WT) and knockout () mice, and proteomic analyses were conducted to identify protein changes between sham and AVF WT tissue. Immunofluorescence and Western blot assays compared venous tissue from WT and mice. In vitro studies using human umbilical vein endothelial cells and human umbilical vein smooth muscle cells examined TNC-siRNA effects on thrombomodulin (THBD) and NF-κB. Macrophages from WT and mice were assessed for anti-inflammatory phenotype polarization and tissue factor expression. TNC expression was spatially and temporally regulated in WT mice with AVF, and TNC colocalized with matrix remodeling but not with THBD expression; TNC expression was downregulated in patent AVF but sustained in occluded AVF, both in WT mice and human AVF specimens. mice had reduced AVF patency, less wall thickening, and increased thrombosis, with increased THBD expression. In vitro, TNC-siRNA increased THBD and reduced NF-κB activation. Macrophages from mice showed increased anti-inflammatory macrophage polarization and tissue factor expression, facilitating thrombosis. Sustained TNC expression drives neointimal hyperplasia and AVF failure by promoting a prothrombotic, inflammatory microenvironment. Targeting TNC pathways may enhance AVF patency and improve dialysis outcomes. This study identifies Tenascin-C (TNC) as a key regulator of arteriovenous fistula (AVF) patency. TNC is spatially and temporally regulated, driving neointimal hyperplasia and thrombosis by promoting a prothrombotic, inflammatory microenvironment. In mice, reduced TNC expression increased thrombomodulin and anti-inflammatory macrophage polarization but impaired wall thickening and AVF patency. These findings link sustained TNC expression to AVF failure and suggest that targeting TNC pathways could enhance AVF outcomes in patients requiring hemodialysis.
终末期肾病（ESKD）影响着美国超过74万人，许多患者因动静脉内瘘（AVF）具有更高的通畅率和更低的感染率，而依赖其进行血液透析。然而，AVF的通畅率会因血栓形成和新生内膜增生而降低，导致其1年通畅率仅为40%-50%。我们推测，腱生蛋白-C（TNC）作为损伤后炎症和免疫反应的调节因子，在AVF成熟过程中也调节静脉重塑。在野生型（WT）和基因敲除（）小鼠中建立AVF，并进行蛋白质组学分析以确定假手术组和AVF WT组织之间的蛋白质变化。免疫荧光和蛋白质印迹分析比较了WT和小鼠的静脉组织。使用人脐静脉内皮细胞和人脐静脉平滑肌细胞进行的体外研究检测了TNC-siRNA对血栓调节蛋白（THBD）和核因子κB（NF-κB）的影响。评估了WT和小鼠巨噬细胞的抗炎表型极化和组织因子表达。在患有AVF的WT小鼠中，TNC表达在空间和时间上受到调节，TNC与基质重塑共定位，但与THBD表达不共定位；在WT小鼠和人类AVF标本中，TNC表达在通畅的AVF中下调，但在闭塞的AVF中持续存在。小鼠的AVF通畅率降低，管壁增厚减少，血栓形成增加，THBD表达增加。在体外，TNC-siRNA增加了THBD并降低了NF-κB的激活。来自小鼠的巨噬细胞显示出抗炎巨噬细胞极化增加和组织因子表达增加，促进了血栓形成。持续的TNC表达通过促进促血栓形成的炎症微环境来驱动新生内膜增生和AVF功能衰竭。靶向TNC途径可能会提高AVF的通畅率并改善透析结果。本研究确定腱生蛋白-C（TNC）是动静脉内瘘（AVF）通畅的关键调节因子。TNC在空间和时间上受到调节，通过促进促血栓形成的炎症微环境来驱动新生内膜增生和血栓形成。在小鼠中，TNC表达降低增加了血栓调节蛋白和抗炎巨噬细胞极化，但损害了管壁增厚和AVF通畅率。这些发现将持续的TNC表达与AVF功能衰竭联系起来，并表明靶向TNC途径可以改善需要血液透析患者的AVF治疗效果。
