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@ARTICLE{TodorovVlgyi:285050,
      author       = {Todorov-Völgyi, Katalin and González-Gallego, Judit and
                      Müller, Stephan A and Todorov, Mihail Ivilinov and Seker,
                      Fatma Burcu and Frerich, Simon and Cernilogar, Filippo M and
                      Schröger, Luise and Malik, Rainer and Cao, Jiayu and
                      Llovera, Gemma and Roth, Stefan and Schillinger, Ulrike and
                      Schifferer, Martina and Reyahi, Azadeh and Crusius, Dennis
                      and Pedro, Liliana D and Simons, Mikael and Carlsson, Peter
                      and Ertürk, Ali and Liesz, Arthur and Schotta, Gunnar and
                      Plesnila, Nikolaus and Lichtenthaler, Stefan F and Paquet,
                      Dominik and Dichgans, Martin},
      title        = {{T}he stroke risk gene {F}oxf2 maintains brain endothelial
                      cell function via {T}ie2 signaling.},
      journal      = {Nature neuroscience},
      volume       = {29},
      number       = {2},
      issn         = {1097-6256},
      address      = {New York, NY},
      publisher    = {Nature America},
      reportid     = {DZNE-2026-00174},
      pages        = {325 - 336},
      year         = {2026},
      abstract     = {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.},
      keywords     = {Animals / Forkhead Transcription Factors: genetics /
                      Forkhead Transcription Factors: metabolism / Endothelial
                      Cells: metabolism / Endothelial Cells: physiology /
                      Receptor, TIE-2: metabolism / Receptor, TIE-2: genetics /
                      Mice / Signal Transduction: physiology / Signal
                      Transduction: genetics / Stroke: genetics / Stroke:
                      metabolism / Brain: metabolism / Humans / Blood-Brain
                      Barrier: metabolism / Mice, Knockout / Male / Cerebral Small
                      Vessel Diseases: genetics / Cerebral Small Vessel Diseases:
                      metabolism / Mice, Inbred C57BL / Forkhead Transcription
                      Factors (NLM Chemicals) / Receptor, TIE-2 (NLM Chemicals) /
                      Tek protein, mouse (NLM Chemicals) / Foxf2 protein, mouse
                      (NLM Chemicals)},
      cin          = {AG Dichgans / AG Lichtenthaler / AG Misgeld / AG Simons},
      ddc          = {610},
      cid          = {I:(DE-2719)5000022 / I:(DE-2719)1110006 /
                      I:(DE-2719)1110000-4 / I:(DE-2719)1110008},
      pnm          = {353 - Clinical and Health Care Research (POF4-353) / 352 -
                      Disease Mechanisms (POF4-352) / 351 - Brain Function
                      (POF4-351)},
      pid          = {G:(DE-HGF)POF4-353 / G:(DE-HGF)POF4-352 /
                      G:(DE-HGF)POF4-351},
      typ          = {PUB:(DE-HGF)16},
      pubmed       = {pmid:41398477},
      pmc          = {pmc:PMC12880920},
      doi          = {10.1038/s41593-025-02136-5},
      url          = {https://pub.dzne.de/record/285050},
}