Endothelial Cell TGF-β (Transforming Growth Factor-Beta) Signaling Regulates Venous Adaptive Remodeling to Improve Arteriovenous Fistula Patency.
Endothelial Cell TGF-β (Transforming Growth Factor-Beta) Signaling Regulates Venous Adaptive Remodeling to Improve Arteriovenous Fistula Patency.
复制标题
内皮细胞TGF-β（转化生长因子β）信号调节静脉适应性重塑改善动静脉瘘通畅
DOI：
10.1161/atvbaha.122.317676
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发表时间：
2022-07
影响因子：
8.7
通讯作者：
Dardik, Alan
中科院分区：
文献类型：
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作者：
Taniguchi, Ryosuke;Ohashi, Yuichi;Lee, Jung Seok;Hu, Haidi;Gonzalez, Luis;Zhang, Weichang;Langford, John;Matsubara, Yutaka;Yatsula, Bogdan;Tellides, George;Fahmy, Tarek M.;Hoshina, Katsuyuki;Dardik, Alan
关键词：
动静脉内瘘（AVF）是血液透析血管通路的金标准。虽然静脉必须扩张和扩张以成功进行血液透析，但壁厚过大会导致狭窄，从而导致AVF失败。由于转化生长因子-β（TGF-β）调节细胞外基质沉积和平滑肌细胞（SMC）增殖，这是壁厚度的关键组成部分，我们假设TGF-β信号转导的破坏可防止静脉重塑期间壁过度增厚。使用小鼠下腔静脉瘘模型。SB 431542是一种TGF-β受体I抑制剂，被封装在纳米颗粒中，并应用于C57 BL/6 J小鼠的AVF外膜。或者，在SMC或内皮细胞中条件性破坏TGF-β受体的小鼠中产生AVF。连续进行多普勒超声检查以确认通畅性并测量血管直径。在预定的时间点收获AVF用于组织学和免疫荧光分析。用含SB 431542的纳米颗粒抑制TGF-β信号传导显著减少了早期成熟阶段（第7-21天）AVF壁中的p-Smad 2阳性细胞，并且与AVF壁厚度降低相关，其显示胶原密度降低和SMC增殖降低。SMC特异性TGF-β信号传导中断降低胶原密度，但不降低SMC增殖或壁厚度。内皮细胞特异性TGF-β信号传导中断降低了AVF壁中的胶原密度和SMC增殖，并与壁厚度减少、外向重塑增加和AVF通畅性改善相关。内皮细胞靶向TGF-β抑制可能是改善AVF通畅性的一种转化策略。
Arteriovenous fistulae (AVF) are the gold standard for vascular access for hemodialysis. Although the vein must thicken and dilate for successful hemodialysis, excessive wall thickness leads to stenosis causing AVF failure. Since transforming growth factor-β (TGF-β) regulates extracellular matrix deposition and smooth muscle cell (SMC) proliferation, critical components of wall thickness, we hypothesized that disruption of TGF-β signaling prevents excessive wall thickening during venous remodeling. A mouse aortocaval fistula model was used. SB431542, an inhibitor of TGF-β receptor I, was encapsulated in nanoparticles and applied to the AVF adventitia in C57BL/6J mice. Alternatively, AVF were created in mice with conditional disruption of TGF-β receptors in either SMC or endothelial cells. Doppler ultrasound was performed serially to confirm patency and to measure vessel diameters. AVF were harvested at predetermined time points for histological and immunofluorescence analyses. Inhibition of TGF-β signaling with SB431542-containing nanoparticles significantly reduced p-Smad2-positive cells in the AVF wall during the early maturation phase (days 7-21) and was associated with decreased AVF wall thickness that showed both decreased collagen density and decreased SMC proliferation. SMC-specific TGF-β signaling disruption decreased collagen density but not SMC proliferation or wall thickness. Endothelial cell-specific TGF-β signaling disruption decreased both collagen density and SMC proliferation in the AVF wall and was associated with reduced wall thickness, increased outward remodeling and improved AVF patency. Endothelial cell-targeted TGF-β inhibition may be a translational strategy to improve AVF patency.