Sex Hormones Impact Early Maturation and Immune Response in the Arteriovenous Fistula Mouse Model.

Arteriovenous fistulae (AVF) fail to mature in female patients compared with male patients, leading to inferior outcomes and decreased utilization. As our mouse AVF model recapitulates sex differences in human AVF maturation, we hypothesized that sex hormones mediate these differences during AVF maturation. C57Bl/6 mice (9-11 week) underwent aortocaval AVF surgery and gonadectomy. AVF hemodynamics were measured via ultrasound (days 0-21). Blood was collected for FACS, and tissue for immunofluorescence and ELISA (days 3,7); wall thickness was assessed using histology (day 21). Inferior vena cava (IVC) shear stress was higher in male mice (p=0.0028) after gonadectomy, and they had increased wall thickness (22.0 ± 1.8 um vs. 12.7 ± 1.2; p<0.0001). Conversely, females had decreased thickness (6.8 ± 0.6 um vs. 15.3 ± 0.9; p=0.0002). Intact females had higher proportions of circulating CD3+ T cells on day 3 (p=0.0043), CD4+ (p=0.0003) and CD8+ T cells (p=0.005) on day 7, and CD11b+ monocytes on day 3 (p = 0.0046). After gonadectomy, these differences disappeared. In the fistula wall of intact female mice, CD3+ T cells (p=0.025), CD4+ T cells (p=0.0178), CD8+ T cells (p=0.0571), and CD68+ macrophages (p=0.0078) increased in the fistula wall on day 3 and 7. This disappeared after gonadectomy. Further, female mice had higher IL-10 (p=0.0217) and TNF-α levels (p=0.0417) in their AVF walls than males. Sex hormones mediate AVF maturation and suggest that hormone receptor signaling may be a target to improve AVF maturation.