Splicing of fibronectin gene contribute to the aneurysmal dilatation of arteriovenous fistula

Patients with end-stage renal disease often require arteriovenous fistula (AVF) creation for hemodialysis. However, nearly 40% of patients develop aneurysmal dilatation of AVF (AVFA) after surgery, which can lead to prolonged bleeding at puncture sites, increased infection risk, and even potential rupture. Despite its high incidence, research on AVFA remains remarkably limited. This study makes an innovative discovery by establishing a link between AVFA formation and alternative splicing of fibronectin (FN), a crucial extracellular matrix component. Specifically, we demonstrate that increased inclusion of the EDA exon in FN within vascular smooth muscle cells triggers phenotypic switching to a synthetic state and extracellular matrix remodeling through the ITGB1/FAK/Src/RUNX2 pathway. These changes ultimately reduce vascular mechanical strength and contribute to AVFA development. Furthermore, we identify the splicing factor SRSF5 as a key regulator of EDA inclusion and characterize its potential binding sites, providing potential therapeutic targets for AVFA prevention.