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Sex Hormones Mediate Sex Differences in Hemodynamics and Inflammation during Arteriovenous Fistula Maturation

Open AccessPublished:June 10, 2022DOI:https://doi.org/10.1016/j.jvssci.2022.05.014

      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 (aged 9-11 months) were treated with sham or aortocaval AVF surgery; some were pretreated with gonadectomy 1 week before surgery. AVF diameter was measured via ultrasound examination (days 0-21). Blood was collected for fluorescent activated cell sorting, and tissue examined using immunofluorescence or enzyme-linked immunosorbent assay (days 3,7); wall thickness was assessed using histology (day 21).

      Results

      At baseline, female and male mice had similar inferior vena cava (IVC) diameters (P = .611) and wall thicknesses (P = .491). After AVF creation, female mice had an increased normalized IVC diameter (P = .0012), flow velocity (P = .0013), and shear stress (P = .002; days 3-21; n = 10); however, there was no difference in wall thickness (female, 15.8 ± 0.2 μm; male, 12.4 ± 2.3 μm; P = .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 = .001; day 3; n = 22) and CD4+ T cells (57.9% ± 2.9% vs 34.5% ± 6.1%; P = .0001). In the AVF wall there were increased CD45+ cells on immunofluorescence in females (22.5 ± 1.5 cells/high-power field vs 13 ± 2 cells/high-power field; P = .063; day 3; n = 4) as well as increased IL-10 immunoreactivity (3.98 ± 0.44 ng/μg vs 2.49 ± 0.47 ng/μg; P = .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 μm vs 12.4 ± 2.3μm; P = .014); conversely, female mice had decreased thickness than intact females (6.1 ± 0.6 μm vs 15.8 ± 0.2μm; P = .005). There was loss of differences among circulating immune cells after gonadectomy (CD11b; P = .0882; CD4; P = .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.