TY  - JOUR
AU  - Todorov-Völgyi, Katalin
AU  - González-Gallego, Judit
AU  - Müller, Stephan A
AU  - Todorov, Mihail Ivilinov
AU  - Seker, Fatma Burcu
AU  - Frerich, Simon
AU  - Cernilogar, Filippo M
AU  - Schröger, Luise
AU  - Malik, Rainer
AU  - Cao, Jiayu
AU  - Llovera, Gemma
AU  - Roth, Stefan
AU  - Schillinger, Ulrike
AU  - Schifferer, Martina
AU  - Reyahi, Azadeh
AU  - Crusius, Dennis
AU  - Pedro, Liliana D
AU  - Simons, Mikael
AU  - Carlsson, Peter
AU  - Ertürk, Ali
AU  - Liesz, Arthur
AU  - Schotta, Gunnar
AU  - Plesnila, Nikolaus
AU  - Lichtenthaler, Stefan F
AU  - Paquet, Dominik
AU  - Dichgans, Martin
TI  - The stroke risk gene Foxf2 maintains brain endothelial cell function via Tie2 signaling.
JO  - Nature neuroscience
VL  - 29
IS  - 2
SN  - 1097-6256
CY  - New York, NY
PB  - Nature America
M1  - DZNE-2026-00174
SP  - 325 - 336
PY  - 2026
AB  - 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.
KW  - Animals
KW  - Forkhead Transcription Factors: genetics
KW  - Forkhead Transcription Factors: metabolism
KW  - Endothelial Cells: metabolism
KW  - Endothelial Cells: physiology
KW  - Receptor, TIE-2: metabolism
KW  - Receptor, TIE-2: genetics
KW  - Mice
KW  - Signal Transduction: physiology
KW  - Signal Transduction: genetics
KW  - Stroke: genetics
KW  - Stroke: metabolism
KW  - Brain: metabolism
KW  - Humans
KW  - Blood-Brain Barrier: metabolism
KW  - Mice, Knockout
KW  - Male
KW  - Cerebral Small Vessel Diseases: genetics
KW  - Cerebral Small Vessel Diseases: metabolism
KW  - Mice, Inbred C57BL
KW  - Forkhead Transcription Factors (NLM Chemicals)
KW  - Receptor, TIE-2 (NLM Chemicals)
KW  - Tek protein, mouse (NLM Chemicals)
KW  - Foxf2 protein, mouse (NLM Chemicals)
LB  - PUB:(DE-HGF)16
C6  - pmid:41398477
C2  - pmc:PMC12880920
DO  - DOI:10.1038/s41593-025-02136-5
UR  - https://pub.dzne.de/record/285050
ER  -