Abstract
Vascular smooth muscle cells (VSMCs) exhibit substantial heterogeneity and plasticity, enabling them to switch between contractile and synthetic states, which is crucial for vascular remodeling. Nexilin (NEXN) has been identified as a high-confidence gene associated with dilated cardiomyopathy. Existing evidence indicates 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 demonstrated NEXN was highly expressed in VSMCs, and the expression of NEXN was 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 VSMC proliferation and phenotypic transition through endoplasmic reticulum (ER) stress and Krüppel-like factor 4 signaling. Inhibiting ER stress ameliorated VSMC 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.
Authors
Zexuan Lin, Chaojie Wang, Zhuohua Wen, Zhaohui Cai, Wenjie Guo, Xin Feng, Zengyan Huang, Rongjun Zou, Xiaoping Fan, Canzhao Liu, Hanyan Yang
Figure 5
VSMC-specific deletion of NEXN aggravates neointima formation following vascular injury in mice.
