Abstract 327: Sex Hormones Mediate Sex Differences In Hemodynamics And Inflammation During Arteriovenous Fistula Maturation

Abstract

Background: Arteriovenous fistulae (AVF) fail to mature, that is dilate and thicken, in women more than in men, leading to inferior outcomes and decreased utilization in women. As our mouse AVF model recapitulates human AVF maturation, including decreased maturation and patency in female mice, we hypothesize that sex hormones mediate sex differences during AVF maturation. Methods: C57Bl/6 mice (9-11 months) were treated with sham or aortocaval AVF surgery; some were pretreated with gonadectomy 1 week prior to surgery. AVF diameter was measured via ultrasound (days 0-21). Blood was collected for FACS, and tissue examined using immunofluorescence or ELISA (days 3,7); wall thickness was assessed using histology (day 21). Results: At baseline, female and male mice had similar inferior vena cava (IVC) diameter (p=0.611) and wall thickness (p=0.491). After AVF creation, female mice had increased normalized IVC diameter (p=0.0012), flow velocity (p=0.0013), and shear stress (p=0.002; days 3-21; n=10); however, there was no difference in wall thickness (female, 15.8±0.2 um; male, 12.4±2.3 um; p=0.638; n=10). There were also increased circulating CD11b+ macrophages in female compared with male mice (31.8 ± 4.0% vs 18.7 ± 1.9%; p=0.001; day 3; n=22) and CD4+ T cells (57.9 ± 2.9% vs 34.5 ± 6.1%, p=0.0001). In the AVF wall there were increased CD45+ cells on immunofluorescence in females (22.5 ± 1.5 cells/hpf vs 13 ± 2 cells/hpf, p=0.063; day 3; n=4) as well as increased IL-10 immunoreactivity (3.98 ± 0.44 ng/ug vs 2.49 ± 0.47 ng/ug; p=0.076). In mice with gonadectomy, baseline IVC diameter, velocity, and shear stress were similar between female and male mice. After gonadectomy, male mice had increased AVF wall thickness than intact males (24.2 ± 1.6 um vs 12.4 ± 2.3; p=0.014); conversely, female mice had decreased thickness than intact females (6.1 ± 0.6 um vs 15.8 ± 0.2; p=0.005). There was loss of differences among circulating immune cells after gonadectomy (CD11b, p=0.0882; CD4, p=0.7095). Conclusions: Sex differences in hemodynamics and inflammation are present during venous remodeling, whereas these differences disappear after gonadectomy. Sex hormones mediate AVF maturation and suggest that hormone receptor signaling may be a target to improve AVF maturation.