biostudies-literatureTodorov-Volgyi KEuropean Research Council325-336https://www.ebi.ac.uk/biostudies/studies/S-EPMC12880920biostudies-literatureUnknown29(2)Cerebral small vessel disease (SVD) is a common chronic cerebrovascular disorder with poorly understood pathomechanisms. Genetic studies have identified FOXF2 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-brain barrier leakage, which worsened after experimental stroke. Proteomic analyses of Foxf2-deficient mouse brain-derived and human-induced pluripotNature neuroscienceThe stroke risk gene Foxf2 maintains brain endothelial cell function via Tie2 signaling.PMC12880920865323Todorov MIGonzalez-Gallego JCernilogar FMCao JPaquet DSeker FBReyahi ASchifferer MLlovera GFrerich SSchillinger UMalik RSchroger LErturk ATodorov-Volgyi KDichgans MPlesnila NLichtenthaler SFCarlsson PSimons MMuller SARoth SLiesz ACrusius DPedro LDSchotta GfalseThe stroke risk gene Foxf2 maintains brain endothelial cell function via Tie2 signaling.Cerebral small vessel disease (SVD) is a common chronic cerebrovascular disorder with poorly understood pathomechanisms. Genetic studies have identified FOXF2 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-brain barrier leakage, which worsened after experimental stroke. Proteomic analyses of Foxf2-deficient mouse brain-derived and human-induced pluripot2026-01-01T00:00:00Z2026 Feb2026-07-15T06:32:12.899Z2026-06-30T03:21:33.599ZS-EPMC128809204139847710.1038/s41593-025-02136-5