G6PD deficiency is implicated in Circle of Willis variants in stroke patients and impairs brain vasculature in zebrafish

Glucose-6-phosphate dehydrogenase (G6PD) deficiency, the most common hereditary enzyme defect in the world, may be involved in cerebrovascular abnormalities suggested by clinical research. However, whether and how G6PD deficiency impairs cerebral vasculature is poorly understood. We therefore aimed at determining the role of G6PD in brain vasculature. By evaluating cerebrovascular imaging data from stroke patients, we found patients with G6PD deficiency exhibited greater morphological variability in the circle of Willis (CoW) with reduced frequency of the anterior communicating artery, bilateral A1 segments, but a higher incidence of fetal posterior cerebral artery (fPCA). To further confirm G6PD deficiency was associated with cerebrovascular abnormalities, we used pharmacological inhibitor to suppress G6PD activity in zebrafish embryos and utilized CRISPR/Cas9 technology to generate <i>g6pd</i> homozygous knockout and endothelial cell-specific knockout zebrafish lines. We found all of these models demonstrated varying degrees of cerebrovascular morphological abnormalities and impairment of cerebrovascular angiogenesis. Transcriptomic data analysis and in vitro experiments further elucidated that G6PD deficiency led to dysfunctional angiogenic response and induced apoptosis. Altogether, we first demonstrated that G6PD deficiency may be associated with CoW variants in stroke patients and impairing cerebrovascular morphology and angiogenesis during zebrafish development.