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Intracerebral Hemorrhage (ICH) is a stroke subtype with high mortality, and its core pathological mechanism involves the disruption of cerebrovascular homeostasis. Genetic factors play a crucial role in ICH pathogenesis, underscoring the importance of identifying core regulatory factors and delineating the associated pathological network. Here, through genome-wide association study (GWAS), we identified synaptopodin (SYNPO) as a genetic susceptibility gene for ICH. SYNPO is an evolutionarily conserved actin-binding protein previously shown to be highly expressed in cerebrovascular endothelial cells, where it regulates the actin cytoskeleton to maintain endothelial junction stability. However, its functional role in ICH remains unclear. To investigate this, we conducted a synpo mutant zebrafish line using CRISPR/Cas9. Following epinephrine challenge, synpo mutant larvae displayed significantly elevated cerebrovascular leakage compared with wild-type controls, and adult mutants showed a markedly higher incidence of ICH. Transcriptomic profiling revealed significant downregulation of the key adhesion gene cdh2 in mutant brains. Subsequent rescue experiments confirmed that cdh2 mRNA supplementation effectively ameliorated the cerebrovascular leakage. In summary, our study unveils a pathway in which synpo maintains cerebrovascular homeostasis by positively regulating cdh2, demonstrating that the synpo-cdh2 axis serves as a key regulatory pathway in ICH. These findings provide insights into the genetic mechanisms underlying ICH and highlight potential therapeutic targets.