Vascular Biology and Therapeutics Program, Yale School of Medicine, New Haven, CT, USA.
Department of Surgery, Yale School of Medicine, New Haven, CT, USA.
Sci Rep. 2017 Nov 13;7(1):15386. doi: 10.1038/s41598-017-13071-2.
Low rates of arteriovenous fistula (AVF) maturation prevent optimal fistula use for hemodialysis; however, the mechanism of venous remodeling in the fistula environment is not well understood. We hypothesized that the embryonic venous determinant Eph-B4 mediates AVF maturation. In human AVF and a mouse aortocaval fistula model, Eph-B4 protein expression increased in the fistula vein; expression of the arterial determinant Ephrin-B2 also increased. Stimulation of Eph-B-mediated signaling with Ephrin-B2/Fc showed improved fistula patency with less wall thickness. Mutagenesis studies showed that tyrosine-774 is critical for Eph-B4 signaling and administration of inactive Eph-B4-Y774F increased fistula wall thickness. Akt1 expression also increased in AVF; Akt1 knockout mice showed reduced fistula diameter and wall thickness. In Akt1 knockout mice, stimulation of Eph-B signaling with Ephrin-B2/Fc showed no effect on remodeling. These results show that AVF maturation is associated with acquisition of dual arteriovenous identity; increased Eph-B activity improves AVF patency. Inhibition of Akt1 function abolishes Eph-B-mediated venous remodeling suggesting that Eph-B4 regulates AVF venous adaptation through an Akt1-mediated mechanism.
动静脉瘘（AVF）成熟率低会阻碍最佳瘘管用于血液透析；然而，瘘管环境中静脉重塑的机制尚不清楚。我们假设胚胎静脉决定因素 Eph-B4 介导 AVF 成熟。在人类 AVF 和小鼠主动脉-腔静脉瘘模型中，Eph-B4 蛋白在瘘管静脉中的表达增加；动脉决定因素 Ephrin-B2 的表达也增加。Ephrin-B2/Fc 刺激 Eph-B 介导的信号转导可改善瘘管通畅性，减少管壁厚度。突变研究表明，酪氨酸-774 对 Eph-B4 信号转导至关重要，而无活性 Eph-B4-Y774F 的给药会增加瘘管壁厚度。Akt1 在 AVF 中的表达也增加；Akt1 基因敲除小鼠显示瘘管直径和壁厚度减小。在 Akt1 基因敲除小鼠中，Ephrin-B2/Fc 刺激 Eph-B 信号转导对重塑没有影响。这些结果表明，AVF 成熟与获得双重动静脉特性有关；增加 Eph-B 活性可改善 AVF 通畅性。抑制 Akt1 功能可消除 Eph-B 介导的静脉重塑，表明 Eph-B4 通过 Akt1 介导的机制调节 AVF 静脉适应。
