Fibroblast reprogramming in the dura mater of NTG-induced migraine-related chronic hypersensitivity model drives monocyte infiltration via Angptl1-dependent stromal signaling

作者：Guangyu Guo, Lei Zhang, Xuyang Liu, Yiping Deng, Peiyu Wu, Ruofan Zhao, Wei Wang · 发表于：The Journal of Headache and Pain · 年份：2025 · DOI：10.1186/s10194-025-02058-4 · 被引用次数：8 · 研究领域：Migraine and Headache Studies、Neuroinflammation and Neurodegeneration Mechanisms、Vestibular and auditory disorders

BACKGROUND: Migraine, characterized by recurrent episodes of severe headache, remains mechanistically enigmatic. While traditional theories emphasize trigeminovascular activation, the role of meningeal stromal-immune crosstalk in disease chronicity is poorly understood. METHODS: A migraine-related chronic hypersensitivity model was utilized via intermittent intraperitoneal nitroglycerin (NTG, 10 mg/kg, every other day for 9 days) and peripheral mechanical hypersensitivity was assessed using von Frey filaments. Single-cell RNA sequencing (scRNA-seq) was performed on dura tissues to construct a cellular atlas of NTG-induced remodeling. These data were then integrated with migraine genome-wide association study (GWAS) risk genes, cell-cell interaction networks, and transcriptional regulation analysis to dissect NTG-driven meningeal remodeling. RESULTS: The NTG-induced migraine-related chronic hypersensitivity model demonstrated sustained mechanical allodynia, as evidenced by significantly decreased paw withdrawal thresholds (p < 0.0001). Single-cell profiling of the dura mater revealed a 2.4-fold expansion of a pro-inflammatory fibroblast subpopulation (Fibro_c5: 1.9% in Vehicle vs. 4.6% in NTG group), which exhibited marked activation of TNF-α/NF-κB signaling pathways (normalized enrichment score [NES] = 1.83). Concomitantly, we observed an 82% increase in meningeal monocytes (5.7-10.4%) that showed preferential interaction with Fibro_c5 fibroblasts through Angptl1-mediated str...