Department of Neurosurgery, The 1st Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, China.
Department of Neurosurgery, Huashan Hospital, Fudan University, Shanghai, China.
Vasc Med. 2024 Feb;29(1):5-16. doi: 10.1177/1358863X231218210.
Intracranial aneurysm (IA) is a common vascular enlargement that occurs in the wall of cerebral vessels and frequently leads to fatal subarachnoid hemorrhage. PDZ and LIM domain protein 1 (PDLIM1) is a cytoskeletal protein that functions as a platform for multiple protein complex formation. However, whether PDLIM is involved in the pathogenesis of IA remains poorly understood.
Loss-of-function and gain-of-function strategies were employed to determine the in vitro roles of PDLIM1 in vascular endothelial cells (VECs). A rat model of IA was generated to study the role of PDLIM1 in vivo. Gene expression profiling, Western blotting, and dual luciferase reporter assays were performed to uncover the underlying cellular mechanism. Clinical IA samples were used to determine the expression of PDLIM1 and its downstream signaling molecules.
PDLIM1 expression was reduced in the endothelial cells of IA and was regulated by Yes-associated protein 1 (YAP1). Genetic silencing of inhibited the viability, migratory ability, and tube formation ability of VECs. Opposite results were obtained by ectopic expression of . Additionally, PDLIM1 overexpression mitigated IA in vivo. Mechanistic investigations revealed that PDLIM1 promoted the transcriptional activity of β-catenin and induced the expression of v-myc myelocytomatosis viral oncogene homolog (MYC) and cyclin D1 (CCND1). In clinical settings, reduced expression of PDLIM1 and β-catenin downstream target genes was observed in human IA samples.
Our study indicates that YAP1-dependent expression of PDLIM1 can inhibit IA development by modulating the activity of the Wnt/β-catenin signaling pathway and that PDLIM1 deficiency in VECs may represent a potential marker of aggressive disease.
颅内动脉瘤（IA）是一种常见的脑血管扩张，发生在脑血管壁，常导致致命性蛛网膜下腔出血。PDZ 和 LIM 结构域蛋白 1（PDLIM1）是一种细胞骨架蛋白，作为多种蛋白质复合物形成的平台发挥作用。然而，PDLIM 是否参与 IA 的发病机制尚不清楚。
采用基因敲除和过表达策略，研究 PDLIM1 在血管内皮细胞（VEC）中的体外作用。建立大鼠 IA 模型，研究 PDLIM1 在体内的作用。通过基因表达谱分析、Western blot 分析和双荧光素酶报告基因检测，揭示其潜在的细胞机制。采用临床 IA 样本，检测 PDLIM1 及其下游信号分子的表达。
IA 内皮细胞中 PDLIM1 表达降低，受 Yes 相关蛋白 1（YAP1）调控。沉默抑制 VEC 的活力、迁移和管腔形成能力。而过表达则相反。此外，PDLIM1 的过表达减轻了体内的 IA。机制研究表明，PDLIM1 促进 β-连环蛋白的转录活性，诱导 v-myc 髓细胞瘤病毒癌基因同源物（MYC）和细胞周期蛋白 D1（CCND1）的表达。在临床环境中，观察到人类 IA 样本中 PDLIM1 和 β-连环蛋白下游靶基因的表达降低。
本研究表明，YAP1 依赖性 PDLIM1 表达可通过调节 Wnt/β-连环蛋白信号通路来抑制 IA 的发生发展，而 VEC 中 PDLIM1 的缺失可能是疾病侵袭性的潜在标志物。
