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

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

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Animals
  • Arteriovenous Shunt, Surgical*
  • Male
  • Mice
  • Mice, Knockout
  • Proto-Oncogene Proteins c-akt / genetics
  • Proto-Oncogene Proteins c-akt / metabolism
  • Receptor, EphB2 / genetics
  • Receptor, EphB2 / metabolism
  • Receptor, EphB4 / genetics
  • Vascular Patency*
  • Vascular Remodeling*

Substances

  • Ephb2 protein, mouse
  • Ephb4 protein, mouse
  • Receptor, EphB2
  • Receptor, EphB4
  • Akt1 protein, mouse
  • Proto-Oncogene Proteins c-akt