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Arterioscler Thromb Vasc Biol. 2019 Apr;39(4):754-764. doi: 10.1161/ATVBAHA.119.312417.

Stimulation of Caveolin-1 Signaling Improves Arteriovenous Fistula Patency.

Hashimoto T1,2,3,4, Isaji T1,2,3,4, Hu H1,2,3, Yamamoto K1,2,3,4, Bai H1,2,3, Santana JM1,2, Kuo A1,5, Kuwahara G1,2, Foster TR1,2,3, Hanisch JJ1,2, Yatsula BA1,2, Sessa WC1,5, Hoshina K4, Dardik A1,2,3.

Author information

1
From the Vascular Biology and Therapeutics Program (T.H., T.I., H.H., K.Y., H.B., J.M.S., A.K., G.K., T.R.F., J.J.H., B.A.Y., W.C.S., A.D.), Yale School of Medicine, New Haven, CT.
2
Department of Surgery (T.H., T.I., H.H., K.Y., H.B., J.M.S., G.K., T.R.F., J.J.H., B.A.Y., A.D.), Yale School of Medicine, New Haven, CT.
3
Department of Surgery, VA Connecticut Healthcare System, West Haven (T.H., T.I., H.H., K.Y., H.B., T.R.F., A.D.).
4
Department of Vascular Surgery, University of Tokyo, Japan (T.H., T.I., K.Y., K.H.).
5
Department of Pharmacology (A.K., W.C.S.), Yale School of Medicine, New Haven, CT.

Abstract

Objective- Arteriovenous fistulae (AVF) are the most common access created for hemodialysis; however, many AVF fail to mature and require repeated intervention, suggesting a need to improve AVF maturation. Eph-B4 (ephrin type-B receptor 4) is the embryonic venous determinant that is functional in adult veins and can regulate AVF maturation. Cav-1 (caveolin-1) is the major scaffolding protein of caveolae-a distinct microdomain that serves as a mechanosensor at the endothelial cell membrane. We hypothesized that Cav-1 function is critical for Eph-B4-mediated AVF maturation. Approach and Results- In a mouse aortocaval fistula model, both Cav-1 mRNA and protein were increased in the AVF compared with control veins. Cav-1 KO (knockout) mice showed increased fistula wall thickening ( P=0.0005) and outward remodeling ( P<0.0001), with increased eNOS (endothelial NO synthase) activity compared with WT (wild type) mice. Ephrin-B2/Fc inhibited AVF outward remodeling in WT mice but not in Cav-1 KO mice and was maintained in Cav-1 RC (Cav-1 endothelial reconstituted) mice (WT, P=0.0001; Cav-1 KO, P=0.7552; Cav-1 RC, P=0.0002). Cavtratin-a Cav-1 scaffolding domain peptide-decreased AVF wall thickness in WT mice and in Eph-B4 het mice compared with vehicle alone (WT, P=0.0235; Eph-B4 het, P=0.0431); cavtratin also increased AVF patency (day 42) in WT mice ( P=0.0275). Conclusions- Endothelial Cav-1 mediates Eph-B4-mediated AVF maturation. The Eph-B4-Cav-1 axis regulates adaptive remodeling during venous adaptation to the fistula environment. Manipulation of Cav-1 function may be a translational strategy to enhance AVF patency.

KEYWORDS:

arteriovenous fistula; caveolin-1; endothelial cells; mice; veins

PMID:
30786746
PMCID:
PMC6436985
[Available on 2020-04-01]
DOI:
10.1161/ATVBAHA.119.312417

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