Home > In process > The stroke risk gene Foxf2 maintains brain endothelial cell function via Tie2 signaling. > print

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024 7 _ |a 10.1038/s41593-025-02136-5
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024 7 _ |a 1097-6256
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024 7 _ |a 1546-1726
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037 _ _ |a DZNE-2026-00174
041 _ _ |a English
082 _ _ |a 610
100 1 _ |a Todorov-Völgyi, Katalin
|0 0009-0007-8073-9524
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245 _ _ |a The stroke risk gene Foxf2 maintains brain endothelial cell function via Tie2 signaling.
260 _ _ |a New York, NY
|c 2026
|b Nature America
336 7 _ |a article
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336 7 _ |a ARTICLE
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520 _ _ |a 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 pluripotent stem cell-derived ECs that lack FOXF2 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.
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650 _ 7 |a Forkhead Transcription Factors
|2 NLM Chemicals
650 _ 7 |a Receptor, TIE-2
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650 _ 7 |a Tek protein, mouse
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650 _ 7 |a Foxf2 protein, mouse
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650 _ 2 |a Animals
|2 MeSH
650 _ 2 |a Forkhead Transcription Factors: genetics
|2 MeSH
650 _ 2 |a Forkhead Transcription Factors: metabolism
|2 MeSH
650 _ 2 |a Endothelial Cells: metabolism
|2 MeSH
650 _ 2 |a Endothelial Cells: physiology
|2 MeSH
650 _ 2 |a Receptor, TIE-2: metabolism
|2 MeSH
650 _ 2 |a Receptor, TIE-2: genetics
|2 MeSH
650 _ 2 |a Mice
|2 MeSH
650 _ 2 |a Signal Transduction: physiology
|2 MeSH
650 _ 2 |a Signal Transduction: genetics
|2 MeSH
650 _ 2 |a Stroke: genetics
|2 MeSH
650 _ 2 |a Stroke: metabolism
|2 MeSH
650 _ 2 |a Brain: metabolism
|2 MeSH
650 _ 2 |a Humans
|2 MeSH
650 _ 2 |a Blood-Brain Barrier: metabolism
|2 MeSH
650 _ 2 |a Mice, Knockout
|2 MeSH
650 _ 2 |a Male
|2 MeSH
650 _ 2 |a Cerebral Small Vessel Diseases: genetics
|2 MeSH
650 _ 2 |a Cerebral Small Vessel Diseases: metabolism
|2 MeSH
650 _ 2 |a Mice, Inbred C57BL
|2 MeSH
700 1 _ |a González-Gallego, Judit
|b 1
700 1 _ |a Müller, Stephan A
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700 1 _ |a Todorov, Mihail Ivilinov
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700 1 _ |a Seker, Fatma Burcu
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700 1 _ |a Frerich, Simon
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700 1 _ |a Cernilogar, Filippo M
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700 1 _ |a Schröger, Luise
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700 1 _ |a Malik, Rainer
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700 1 _ |a Cao, Jiayu
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700 1 _ |a Llovera, Gemma
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700 1 _ |a Roth, Stefan
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700 1 _ |a Schillinger, Ulrike
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700 1 _ |a Schifferer, Martina
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700 1 _ |a Reyahi, Azadeh
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700 1 _ |a Crusius, Dennis
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700 1 _ |a Simons, Mikael
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700 1 _ |a Carlsson, Peter
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700 1 _ |a Ertürk, Ali
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700 1 _ |a Liesz, Arthur
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700 1 _ |a Schotta, Gunnar
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700 1 _ |a Plesnila, Nikolaus
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700 1 _ |a Lichtenthaler, Stefan F
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700 1 _ |a Paquet, Dominik
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700 1 _ |a Dichgans, Martin
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773 _ _ |a 10.1038/s41593-025-02136-5
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