Zhou Jiabin, Lei Yu, Zhang Shilin, Qin Renwu, Liu Yuhan, Yi Dongye
Department of Neurosurgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, People's Republic of China.
Zhongnan Hospital, Wuhan University, Wuhan, People's Republic of China.
FASEB J. 2025 Mar 31;39(6):e70461. doi: 10.1096/fj.202401445R.
Moyamoya disease (MMD) is a chronic occlusive cerebrovascular ailment with a progressively rising incidence, yet its precise etiology and pathogenesis remain elusive. Adult MMD-related datasets GSE189993 and GSE157628 were procured from the GEO database for screening of differentially expressed genes (DEGs). Weighted gene co-expression network analysis (WGCNA) was employed to unveil the most significant module associated with MMD. Least absolute shrinkage and selection operator (LASSO) logistic regression was used to identify and validate diagnostic markers for MMD. CIBERSORT and ssGSEA analyses were conducted to estimate immune cell infiltration in MMD vessels. In vitro experiments were performed to validate the biological functions of Sphingosine-1-phosphate receptor 1 (S1PR1) in mouse aortic smooth muscle cells (MOVAS). A total of 436 DEGs were identified from GSE189993, comprising 202 up-regulated genes and 234 down-regulated genes. Within the green-yellow module, 87 genes overlapped with DEGs, and 6 genes were identified by Cytoscape as key factors in the pathophysiology of MMD, namely, platelet endothelial cell adhesion molecule 1 (PECAM1), von Willebrand factor (VWF), intercellular cell adhesion molecule 1 (ICAM1), vascular endothelial growth factor C (VEGFC), tissue-type plasminogen activator (PLAT), and S1PR1. Gene Ontology (GO), and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses also showed that key genes were mainly involved in endothelial cells and cell adhesion-related biological function. About 13 diagnostic genes were obtained by the LASSO regression algorithm, with S1PR1 emerging as a hub gene demonstrating good diagnostic performance in both the test set and validation set. Finally, we validated that overexpression of S1PR1 spurred viability, proliferation, and cell division in mouse aortic smooth muscle cells (MOVAS) and human cerebral vascular smooth muscle cells (HCVSMC) by activating the PI3K/AKT signaling pathway. S1PR1 has been identified as a hub gene for MMD. S1PR1 overexpression has been linked to enhanced cell division and proliferation in vitro, suggesting its potential as a therapeutic target for adult MMD.
烟雾病（MMD）是一种慢性闭塞性脑血管疾病，发病率呈逐渐上升趋势，但其确切病因和发病机制仍不清楚。从基因表达综合数据库（GEO数据库）中获取了与成人MMD相关的数据集GSE189993和GSE157628，用于筛选差异表达基因（DEG）。采用加权基因共表达网络分析（WGCNA）来揭示与MMD相关的最显著模块。使用最小绝对收缩和选择算子（LASSO）逻辑回归来识别和验证MMD的诊断标志物。进行了CIBERSORT和单样本基因集富集分析（ssGSEA）以评估MMD血管中的免疫细胞浸润。进行了体外实验以验证1-磷酸鞘氨醇受体1（S1PR1）在小鼠主动脉平滑肌细胞（MOVAS）中的生物学功能。从GSE189993中总共鉴定出436个DEG，包括202个上调基因和234个下调基因。在绿黄模块中，有87个基因与DEG重叠，并且通过Cytoscape鉴定出6个基因是MMD病理生理学中的关键因子，即血小板内皮细胞黏附分子1（PECAM1）、血管性血友病因子（VWF）、细胞间黏附分子1（ICAM1）、血管内皮生长因子C（VEGFC）、组织型纤溶酶原激活剂（PLAT）和S1PR1。基因本体论（GO）和京都基因与基因组百科全书（KEGG）富集分析还表明，关键基因主要参与内皮细胞和细胞黏附相关的生物学功能。通过LASSO回归算法获得了约13个诊断基因，其中S1PR1作为枢纽基因在测试集和验证集中均表现出良好的诊断性能。最后，我们验证了S1PR1的过表达通过激活PI3K/AKT信号通路促进了小鼠主动脉平滑肌细胞（MOVAS）和人脑血管平滑肌细胞（HCVSMC）的活力、增殖和细胞分裂。S1PR1已被鉴定为MMD的枢纽基因。S1PR1的过表达与体外增强的细胞分裂和增殖有关，表明其作为成人MMD治疗靶点的潜力。
