Lin Zexuan, Wang Chaojie, Wen Zhuohua, Cai Zhaohui, Guo Wenjie, Feng Xin, Huang Zengyan, Zou Rongjun, Fan Xiaoping, Liu Canzhao, Yang Hanyan
Department of Cardiology, Laboratory of Heart Center, Translational Medicine Research Center, Zhujiang Hospital, Southern Medical University, Guangzhou, China.
Guangdong Provincial Key Laboratory of Cardiac Function and Microcirculation, Guangdong Provincial Biomedical Engineering Technology Research Center for Cardiovascular Disease, Guangzhou, China.
JCI Insight. 2025 May 29;10(13). doi: 10.1172/jci.insight.190089. eCollection 2025 Jul 8.
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.
血管平滑肌细胞（VSMCs）表现出显著的异质性和可塑性，使其能够在收缩状态和合成状态之间转换，这对血管重塑至关重要。Nexilin（NEXN）已被确定为与扩张型心肌病相关的高可信度基因。现有证据表明NEXN参与VSMCs的表型转换。然而，对NEXN在血管重塑中细胞特异性作用和精确机制的全面理解仍然难以捉摸。通过整合转录组学分析和平滑肌特异性谱系追踪小鼠，我们证明NEXN在VSMCs中高表达，并且在VSMCs表型转化和血管损伤诱导的内膜增生过程中，NEXN的表达显著降低。VSMC特异性NEXN缺陷促进了VSMCs的表型转变，并加剧了小鼠血管损伤后的内膜增生。机制上，我们发现NEXN主要通过内质网（ER）应激和Krüppel样因子4信号介导VSMC增殖和表型转变。抑制ER应激可通过降低NEXN缺陷引起的细胞周期活性和增殖来改善VSMC表型转变。这些发现表明，靶向NEXN有望成为治疗增殖性动脉疾病的一种有前景的治疗方法。
