Eph-B4 regulates adaptive venous remodeling to improve arteriovenous fistula patency.
Eph-B4 regulates adaptive venous remodeling to improve arteriovenous fistula patency.
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DOI：
10.1038/s41598-017-13071-2
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发表时间：
2017-11-13
影响因子：
4.6
通讯作者：
Dardik A
中科院分区：
文献类型：
--
作者：
Protack CD;Foster TR;Hashimoto T;Yamamoto K;Lee MY;Kraehling JR;Bai H;Hu H;Isaji T;Santana JM;Wang M;Sessa WC;Dardik A
动静脉内瘘（AVF）成熟率较低，妨碍了血液透析中使用最佳内瘘;然而，内瘘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子Eph-B4介导AVF成熟。在人类AVF和小鼠下腔静脉瘘模型中，瘘静脉中Eph-B4蛋白表达增加;动脉决定因子Ephrin-B2的表达也增加。用Ephrin-B2/Fc刺激Eph-B介导的信号传导显示出改善的瘘管通畅性，具有更小的壁厚度。突变研究显示酪氨酸-774对于Eph-B4信号传导是关键的，并且施用无活性的Eph-B4-Y 774 F增加了瘘管壁厚度。AVF中Akt 1表达也增加; Akt 1敲除小鼠显示瘘管直径和管壁厚度减少。在Akt 1敲除小鼠中，用Ephrin-B2/Fc刺激Eph-B信号传导对重塑没有影响。这些结果表明，AVF成熟与获得双重动静脉特性相关; Eph-B活性增加可改善AVF通畅性。抑制Akt 1功能可消除Eph-B介导的静脉重塑，表明Eph-B4通过Akt 1介导的机制调节AVF静脉适应。
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.
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影响因子：
2.2
作者：
Lu, Daniel Y.;Chen, Elizabeth Y.;Wong, Daniel J.;Yamamoto, Kota;Protack, Clinton D.;Williams, Willis T.;Assi, Roland;Hall, Michael R.;Sadaghianloo, Nirvana;Dardik, Alan
通讯作者：
Dardik, Alan
影响因子：
4.7
作者：
Alam, Syed Mahfuzul;Fujimoto, Jiro;Tamaya, Teruhiko
通讯作者：
Tamaya, Teruhiko
影响因子：
2.4
作者：
Lin, Yuankai;Jiang, Weiya;Wang, Rong A.
通讯作者：
Wang, Rong A.
影响因子：
4.3
作者：
Gibson, KD;Gillen, DL;Stehman-Breen, CO
通讯作者：
Stehman-Breen, CO
影响因子：
4.3
作者：
Owens, Christopher D.;Rybicki, Frank J.;Conte, Michael S.
通讯作者：
Conte, Michael S.