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Sci Rep. 2017 Nov 13;7(1):15386. doi: 10.1038/s41598-017-13071-2.

Eph-B4 regulates adaptive venous remodeling to improve arteriovenous fistula patency.

Protack CD1,2,3, Foster TR1,2,3, Hashimoto T1,2,3,4, Yamamoto K1,2,3,4, Lee MY1,5, Kraehling JR1,5, Bai H1,2,3, Hu H1,2,3, Isaji T1,2,4, Santana JM1,2, Wang M1,2, Sessa WC1,5, Dardik A6,7,8.

Author information

1
Vascular Biology and Therapeutics Program, Yale School of Medicine, New Haven, CT, USA.
2
Department of Surgery, Yale School of Medicine, New Haven, CT, USA.
3
Department of Surgery, VA Connecticut Healthcare System, West Haven, CT, USA.
4
Department of Vascular Surgery, The University of Tokyo, Tokyo, Japan.
5
Department of Pharmacology, Yale School of Medicine, New Haven, CT, USA.
6
Vascular Biology and Therapeutics Program, Yale School of Medicine, New Haven, CT, USA. alan.dardik@yale.edu.
7
Department of Surgery, Yale School of Medicine, New Haven, CT, USA. alan.dardik@yale.edu.
8
Department of Surgery, VA Connecticut Healthcare System, West Haven, CT, USA. alan.dardik@yale.edu.

Abstract

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.

PMID:
29133876
PMCID:
PMC5684317
DOI:
10.1038/s41598-017-13071-2
[Indexed for MEDLINE]
Free PMC Article

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