PC236. Cav-1 Regulates EphB4-Mediated Arteriovenous Fistula Maturation

Abstract

Arteriovenous fistula (AVF) continues to be the most common access created for hemodialysis. However, many AVFs fail to mature, suggesting a need to improve AVF maturation. Caveolin1 (Cav-1) is the major scaffolding protein of caveolae, a distinct microdomain that serves as a flow-activated mechanosensor at the membrane of endothelial cells; Eph-B4 is the embryonic venous determinant. We have previously shown that Cav-1 is a mechanism of Eph-B4-mediated vessel remodeling in the murine vein graft model. We have also shown that Eph-B4 expression increases during AVF maturation and Eph-B4 activity inhibits venous remodeling in the murine AVF model. Then we hypothesized that Cav-1 is a critical regulator of Eph-B4-mediated AVF maturation through inhibition of eNOS activity. We used a mouse aortocaval fistula model. The venous AVF limb and control (sham) inferior vena cava (IVC) of wild-type C57BL/6 (WT) were compared for Cav-1 expression. AVFs of WT mice, Cav-1 knockout (KO) mice, Cav-1 endothelial reconstituted (RC) mice, and Eph-B4 heterozygous (Eph-B4 het) mice were analyzed. A Cav-1 scaffolding domain peptide (cavtratin) was administrated to stimulate Cav-1 signaling; ephrinB2/Fc was used to stimulate Eph-B4 signaling. Vessel remodeling was assessed postoperatively by serial ultrasound measurements of the IVC/AVF diameter. AVFs were harvested at day 21 and examined with histology; IVC wall thickness was measured by computerized morphometry. Both Cav-1 mRNA and protein were increased in the fistula veins compared with control veins. Cav-1 KO mice showed enhanced venous remodeling with increased eNOS activity compared with WT mice. Inhibition of remodeling by ephrin-B2/Fc in WT mice was abolished in Cav-1 KO mice, but maintained in Cav-1 RC mice (Fig A). Administration of cavtratin decreased the fistula wall thickness in WT mice as well as in Eph-B4 het mice (Fig B). Endothelial Cav-1 is a critical regulator of Eph-B4-mediated AVF maturation. Manipulation of Cav-1 function may improve arteriovenous maturation within the fistula environment.