From the Department of Vascular and Thyroid Surgery, The First Hospital of China Medical University, Shenyang (H.H.).
Department of Surgery (H.H., S.-R.L., H.B., J.G., T.H., T.I., X.G., T.W., K.W., S.L., S.O., B.Y., A.D.), Yale University School of Medicine, New Haven, CT.
Arterioscler Thromb Vasc Biol. 2020 Jul;40(7):e203-e213. doi: 10.1161/ATVBAHA.119.313848. Epub 2020 May 28.
Arteriovenous fistulae (AVF) are the optimal conduit for hemodialysis access but have high rates of primary maturation failure. Successful AVF maturation requires wall thickening with deposition of ECM (extracellular matrix) including collagen and fibronectin, as well as lumen dilation. TAK1 (TGFβ [transforming growth factor-beta]-activated kinase 1) is a mediator of noncanonical TGFβ signaling and plays crucial roles in regulation of ECM production and deposition; therefore, we hypothesized that TAK1 regulates wall thickening and lumen dilation during AVF maturation. Approach and Results: In both human and mouse AVF, immunoreactivity of TAK1, JNK (c-Jun N-terminal kinase), p38, collagen 1, and fibronectin was significantly increased compared with control veins. Manipulation of TAK1 in vivo altered AVF wall thickening and luminal diameter; reduced TAK1 function was associated with reduced thickness and smaller diameter, whereas activation of TAK1 function was associated with increased thickness and larger diameter. Arterial magnitudes of laminar shear stress (20 dyne/cm) activated noncanonical TGFβ signaling including TAK1 phosphorylation in mouse endothelial cells.
TAK1 is increased in AVF, and TAK1 manipulation in a mouse AVF model regulates AVF thickness and diameter. Targeting noncanonical TGFβ signaling such as TAK1 might be a novel therapeutic approach to improve AVF maturation.
动静脉瘘（AVF）是血液透析通路的最佳通道，但存在较高的原发性成熟失败率。AVF 的成功成熟需要壁增厚，细胞外基质（ECM）沉积，包括胶原蛋白和纤维连接蛋白，以及管腔扩张。TAK1（转化生长因子-β（TGFβ）激活激酶 1）是非经典 TGFβ信号的介质，在 ECM 产生和沉积的调节中发挥关键作用；因此，我们假设 TAK1 调节 AVF 成熟过程中的壁增厚和管腔扩张。方法和结果：在人类和小鼠的 AVF 中，TAK1、JNK（c-Jun N-末端激酶）、p38、胶原蛋白 1 和纤维连接蛋白的免疫反应性与对照静脉相比显著增加。体内 TAK1 的操纵改变了 AVF 壁的厚度和管腔直径；TAK1 功能降低与厚度减小和直径减小相关，而 TAK1 功能的激活与厚度增加和直径增大相关。动脉层流剪切应力（20 达因/平方厘米）激活了包括 TAK1 磷酸化在内的非经典 TGFβ信号，在小鼠内皮细胞中。结论：TAK1 在 AVF 中增加，TAK1 在小鼠 AVF 模型中的操纵调节 AVF 的厚度和直径。靶向非经典 TGFβ信号，如 TAK1，可能是改善 AVF 成熟的一种新的治疗方法。
