EGR1-associated inflammatory and neurovascular mechanisms linking migraine with ischemic stroke risk

Abstract Background Migraine is associated with an increased risk of ischemic stroke, but the molecular mechanisms linking these two disorders remain unclear. Methods We performed an integrated analysis of bulk RNA-seq data from ischemic stroke and single-cell RNA-seq data from a mouse migraine model. Differential expression, Gene Ontology enrichment, cell-cell communication, protein-protein interaction, disease association, and drug-gene interaction analyses were conducted to identify shared molecular signatures and pathways. A nitroglycerin-induced migraine mouse model was further used to validate neurovascular alterations in vivo. Results Integrated transcriptomic analysis identified shared upregulated genes between migraine and ischemic stroke, with IL1B and EGR1 emerging as key candidates. In ischemic stroke, enriched pathways were mainly related to immune and inflammatory responses, particularly immune response-regulating cell surface receptor signaling and interleukin-1-mediated signaling, with IL1B and EGR1 serving as central nodes. Single-cell analysis showed that EGR1 was the only significantly shared upregulated gene in migraine, with elevated expression in PEP neurons, NF neurons, vascular cells, and fibroblasts, while the interleukin-1 production pathway was activated in most of these cell types. Cell-cell communication analysis revealed enhanced interactions among neuronal, vascular, and fibroblast populations, especially through ANGPTL signaling. Hub network analysis identified EGR1, IL1B, TLR4, and ANGPTL2 as core molecules. In vivo, the migraine model showed increased neuronal activation, persistent mechanical hypersensitivity, and reduced ZO-1 expression in the trigeminocervical complex, indicating vascular tight junction impairment. Conclusion These findings suggest that EGR1-associated interleukin-1 inflammatory signaling and enhanced neurovascular-fibroblast communication may link migraine to increased ischemic stroke risk. This study highlights a potential neuroinflammatory and vascular mechanism underlying stroke susceptibility in migraine and suggests candidate therapeutic targets.