Sox17 mediates venous adaptive remodeling after arteriovenous fistula creation.

Objective: Mature arteriovenous fistulae (AVF) are the gold standard vascular access allowing hemodialysis for patients with end-stage kidney disease. The rate of AVF failure remains high, reflecting an incomplete understanding of the biology of AVF maturation and failure. Sox17 is a transcription factor indispensable for the acquisition and maintenance of endothelial arterial identity. Because endothelial cells (EC) acquire dual arteriovenous identity after AVF creation, we determined whether Sox17 mediates venous remodeling in AVF. Methods: Human preaccess vein, failed AVF, and mature AVF from second stage basilic vein transpositions were analyzed using immunofluorescence and single cell sequencing to determine Sox17 expression. Aortocaval AVF created in 9- to 11-week-old C57BL/6J mice were harvested on day 7 or 21 for analysis with Western blot, quantitative polymerase chain reaction, histology, or immunofluorescence to assess Sox17 immunoreactivity in EC. Doppler ultrasound examination confirmed AVF patency and measured inferior vena cava and aortic flow velocity and diameter. Sox17 knockdown was performed using short hairpin RNA lentivirus delivered perivascularly immediately after AVF creation. Analysis of variance and t tests were used for statistical analyses. Results: Sox17 was significantly elevated in mature human AVF compared with control veins (P = .02) and in mature human AVF compared with failed human AVF (P = .04). In the mouse AVF, Sox17 expression was also significantly upregulated compared with sham-operated mice (P = .0012 in male mice; P = .0062 in female mice). Sox17 immunoreactivity was highest on days 7 and 21 and returned to near sham levels at day 42. In both human and mouse AVF, Sox17 expression was localized to the nucleus of EC. Sox17 knockdown mice had impaired venous remodeling, characterized by a smaller inferior vena cava diameter (P = .001) and thinner intima-media layers relative to control AVF (P = .015). Sox17 knockdown mice had decreased JAG1 expression (P = .008) and decreased smooth muscle cell proliferation (P = .03) on day 7. Conclusions: Sox17 is a novel mediator of venous remodeling during AVF maturation. Sox17 is upregulated in the venous outflow of AVF, and Sox17 knockdown causes impaired outward remodeling and wall thickening. Manipulation of endothelial vascular identity may be a translational approach to regulate venous remodeling and improve AVF patency. Clinical Relevance: Arteriovenous fistula (AVF) failure remains a major barrier to long-term hemodialysis access in patients with end-stage kidney disease. This study identifies Sox17 as a key transcription factor mediating venous remodeling after AVF creation. Sox17 expression is elevated in mature human AVF and affects outward remodeling, wall thickening, and smooth muscle cell proliferation in a murine model. Sox17 knockdown results in impaired AVF maturation. These findings highlight Sox17 as a critical regulator of flow-mediated vascular adaptation and suggest that modulation of endothelial arterial identity through Sox17 may represent a novel therapeutic strategy to improve AVF outcomes.