Tudor-SN exacerbates pathological vascular remodeling by promoting the polyubiquitination of PTEN via NEDD4-1

Background: Dysregulation of vascular homeostasis contributes to the development of cardiovascular diseases and increases global mortality. While lineage-tracing studies highlight the critical role of modulated vascular smooth muscle cells (VSMCs) in pathological vascular remodeling, the exact mechanisms remain poorly understood.

Methods: Tudor-SN expression was analyzed in VSMCs from stenotic arteries, PDGF-BB-treated VSMCs, and atherosclerotic plaques. Both loss- and gain-of-function experiments were employed to assess the impact of Tudor-SN on VSMC phenotypic modulation in vivo and in vitro.

Results: Our study shows that Tudor-SN expression is markedly elevated in injured arteries, atherosclerotic plaques, and PDGF-BB-stimulated VSMCs. Tudor-SN deficiency mitigates, whereas its overexpression exacerbates, the phenotypic switching of VSMCs and pathological vascular remodeling. Additionally, the loss of Tudor-SN reduces atherosclerotic plaque formation and enhances plaque stability. Mechanistically, PTEN—a key regulator of the MAPK and PI3K-AKT pathways—plays a central role in Tudor-SN-mediated VSMC proliferation and migration. Tudor-SN promotes PTEN degradation through NEDD4-1-mediated polyubiquitination, aggravating vascular remodeling under pathological conditions. Notably, the PTEN inhibitor BpV(HOpic) reverses the protective effects of Tudor-SN deficiency on VSMC proliferation and migration, as well as the inhibitory effects on vascular remodeling following carotid artery injury in mice.

Conclusions: These findings demonstrate that Tudor-SN deficiency improves pathological vascular remodeling by inhibiting NEDD4-1-dependent PTEN degradation, highlighting Tudor-SN as a potential therapeutic target for preventing vascular diseases.