NEXN regulates vascular smooth muscle cells phenotypic switching and neointimal hyperplasia

Vascular smooth muscle cells (VSMCs) exhibit significant heterogeneity and plasticity, enabling them to switch between contractile and synthetic states, which is crucial for vascular remodeling. NEXN has been identified as a high confidence gene associated with dilated cardiomyopathy (DCM). Existing evidence indicate NEXN is involved in phenotypic switching of VSMCs. However, a comprehensive understanding of the cell - specific roles and precise mechanisms of NEXN in vascular remodeling remains elusive. Using integrative transcriptomics analysis and smooth muscle specific lineage tracing mice, we demonstrate NEXN is highly expressed in VSMCs, and the expression of NEXN is significantly reduced during the phenotypic transformation of VSMCs and intimal hyperplasia induced by vascular injury. VSMC - specific NEXN deficiency promoted the phenotypic transition of VSMCs and exacerbated neointimal hyperplasia in mice following vascular injury. Mechanistically, we found NEXN primarily mediated VSMCs proliferation and phenotypic transition through endoplasmic reticulum (ER) stress and KLF4 signaling. Inhibiting ER stress ameliorated VSMCs phenotypic transition by reducing cell cycle activity and proliferation caused by NEXN deficiency. These findings indicate targeting NEXN could be explored as a promising therapeutic approach for proliferative arterial diseases.