Vascular Biology and Therapeutics Program (R.T., Y.O., H.H., L.G., W.Z., J.L., Y.M., B.Y., G.T., A.D.), Yale School of Medicine, New Haven, CT.
Division of Vascular Surgery, The University of Tokyo, Japan (R.T., Y.O., K.H.).
Arterioscler Thromb Vasc Biol. 2022 Jul;42(7):868-883. doi: 10.1161/ATVBAHA.122.317676. Epub 2022 May 5.
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 TGF-β (transforming growth factor-beta) regulates ECM (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, AVFs were created in mice with conditional disruption of TGF-β receptors in either SMCs or endothelial cells. Doppler ultrasound was performed serially to confirm patency and to measure vessel diameters. AVFs 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.
动静脉瘘（AVF）是血液透析血管通路的金标准。虽然静脉必须变厚和扩张才能成功进行血液透析，但过度的壁厚度会导致狭窄，从而导致 AVF 失败。由于 TGF-β（转化生长因子-β）调节细胞外基质（ECM）沉积和平滑肌细胞（SMC）增殖——这是壁厚度的关键组成部分——我们假设破坏 TGF-β 信号会阻止静脉重塑过程中的过度壁增厚。
使用小鼠主动脉-腔静脉瘘模型。将 TGF-β 受体 I 的抑制剂 SB431542 包裹在纳米颗粒中，并应用于 C57BL/6J 小鼠的 AVF 外膜。或者，在 SMC 或内皮细胞中条件性破坏 TGF-β 受体的小鼠中创建 AVF。使用多普勒超声连续进行以确认通畅性并测量血管直径。在预定的时间点收获 AVF 进行组织学和免疫荧光分析。
用含有 SB431542 的纳米颗粒抑制 TGF-β 信号显著减少了 AVF 壁中的 p-Smad2 阳性细胞在早期成熟阶段（第 7-21 天），并与 AVF 壁厚度降低有关，这表明胶原密度降低和 SMC 增殖减少。SMC 特异性 TGF-β 信号中断减少了胶原密度，但不减少 SMC 增殖或壁厚度。内皮细胞特异性 TGF-β 信号中断减少了 AVF 壁中的胶原密度和 SMC 增殖，并与壁厚度降低、向外重塑增加和 AVF 通畅性改善有关。
内皮细胞靶向 TGF-β 抑制可能是改善 AVF 通畅性的转化策略。
