Stimulation of Caveolin-1 Signaling Improves Arteriovenous Fistula Patency

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 is the embryonic venous determinant that is functional in adult veins and can regulate AVF maturation. Caveolin-1 (Cav-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 to control veins. Cav-1 KO mice showed increased fistula wall thickening (p=0.0005) and outward remodeling (p<0.0001), with increased eNOS activity compared with WT mice. Ephrin-B2/Fc inhibited AVF outward remodeling in WT mice but not in Cav-1 KO mice, and was maintained in Cav-1 endothelial reconstituted (RC) 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 as well as in Eph-B4 het mice compared to 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.

Graphical Abstract