EGR1-associated inflammatory and neurovascular signatures suggest a potential link between migraine and ischemic stroke

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 emerging as prominent candidates in the enriched network context. 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. Network analysis highlighted EGR1, IL1B, TLR4, and ANGPTL2 as candidate hub-associated 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 identify shared inflammatory and neurovascular signatures across migraine-related and ischemic stroke-related datasets, with EGR1 emerging as a candidate molecule associated with these convergent changes. Our results support a hypothesis-generating model in which inflammatory signaling and altered neurovascular communication may represent potential links between migraine and stroke-related vascular vulnerability. Further functional studies are required to determine whether EGR1 or related pathways play a causal role.