RBMS1 Contributes to Early Arteriovenous Fistula Neointimal Remodeling Through Modulation of VSMC Phenotypic Responses

Arteriovenous fistula (AVF) creation initiates stage-dependent remodeling of the venous outflow tract. Neointimal hyperplasia is a common component of this response, but its post-transcriptional regulation remains unclear. Here, analyses of human AVF datasets and tissue specimens characterized RNA-binding motif single-stranded interacting protein 1 (RBMS1) expression in postoperative AVFs, whereas a day-14 mouse AVF model and cultured vascular smooth muscle cells (VSMCs) were used to investigate its role in early neointimal remodeling. Smooth muscle-targeted RBMS1 overexpression aggravated neointimal formation, whereas conditional RBMS1 deletion attenuated it in murine AVFs. In cultured VSMCs, RBMS1 overexpression enhanced proliferation, migration, and the transition from contractile to synthetic marker expression, whereas RBMS1 silencing produced the opposite effects. Mechanistically, RBMS1 bound myelin protein zero-like 1 (MPZL1) mRNA and promoted exon 5 skipping, generating the MPZL1-Δ5 isoform. MPZL1-Δ5 overexpression reproduced selected RBMS1-associated VSMC responses and increased neointimal hyperplasia in vivo, including in RBMS1-deficient mice. MPZL1-Δ5 further interacted with GTPase-activating protein SH3 domain-binding protein 1 (G3BP1) and enhanced protein kinase B (AKT) activation, whereas G3BP1 silencing attenuated RBMS1- or MPZL1-Δ5-induced VSMC responses. Together, these findings identify the RBMS1-MPZL1-Δ5-G3BP1-AKT pathway as an important VSMC-associated mechanism contributing to neointimal remodeling during the early postoperative phase of experimental AVFs.