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Genetic studies have identified\n                    <jats:italic>FOXF2<\/jats:italic>\n                    as a major risk gene for both SVD and stroke. FOXF2 encodes a transcription factor primarily expressed in brain pericytes and endothelial cells (ECs); however, its mechanistic role in cerebrovascular disease remains unknown. Here we show that Foxf2 maintains EC function through Tie2 signaling. RNA and chromatin sequencing identified FOXF2 as a transcriptional activator of Tie2 and other endothelial lineage-specific genes. The deletion of EC-specific Foxf2 in adult mice resulted in blood\u2013brain barrier leakage, which worsened after experimental stroke. Proteomic analyses of Foxf2-deficient mouse brain-derived and human-induced pluripotent stem cell-derived ECs that lack\n                    <jats:italic>FOXF2<\/jats:italic>\n                    revealed a downregulation of multiple proteins involved in Tie2 signaling. Endothelial Foxf2 deficiency impaired functional hyperemia, reduced NO production and increased infarct size through disrupted Tie2 signaling, effects that were rescued by pharmacological activation of Tie2 with AKB-9778. Collectively, our results highlight the critical role of Foxf2-regulated Tie2 signaling in SVD and stroke, suggesting new avenues for therapeutic interventions.\n                  <\/jats:p>","DOI":"10.1038\/s41593-025-02136-5","type":"journal-article","created":{"date-parts":[[2025,12,15]],"date-time":"2025-12-15T10:02:14Z","timestamp":1765792934000},"page":"325-336","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":8,"title":["The stroke risk gene Foxf2 maintains brain endothelial cell function via Tie2 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