ORCID: https://orcid.org/0009-0007-8073-9524; González-Gallego, Judit; Müller, Stephan A. ORCID: https://orcid.org/0000-0003-3414-307X; Todorov, Mihail Ivilinov ORCID: https://orcid.org/0000-0002-8627-1260; Seker, Fatma Burcu; Frerich, Simon ORCID: https://orcid.org/0000-0002-8275-6113; Cernilogar, Filippo M. ORCID: https://orcid.org/0000-0003-2814-3436; Schröger, Luise ORCID: https://orcid.org/0000-0002-6213-4202; Malik, Rainer ORCID: https://orcid.org/0000-0001-9212-2520; Cao, Jiayu ORCID: https://orcid.org/0000-0002-8826-2595; Llovera, Gemma ORCID: https://orcid.org/0000-0002-7509-7500; Roth, Stefan ORCID: https://orcid.org/0000-0001-6823-2981; Schillinger, Ulrike ORCID: https://orcid.org/0009-0005-5513-4692; Schifferer, Martina ORCID: https://orcid.org/0000-0002-0500-8218; Reyahi, Azadeh; Crusius, Dennis; Pedro, Liliana D.; Simons, Mikael ORCID: https://orcid.org/0000-0001-5329-192X; Carlsson, Peter; Ertürk, Ali ORCID: https://orcid.org/0000-0001-5163-5100; Liesz, Arthur ORCID: https://orcid.org/0000-0002-9069-2594; Schotta, Gunnar ORCID: https://orcid.org/0000-0003-4940-6135; Plesnila, Nikolaus ORCID: https://orcid.org/0000-0001-8832-228X; Lichtenthaler, Stefan F. ORCID: https://orcid.org/0000-0003-2211-2575; Paquet, Dominik ORCID: https://orcid.org/0000-0003-2065-1639 und Dichgans, Martin ORCID: https://orcid.org/0000-0002-0654-387X
(2026):
The stroke risk gene Foxf2 maintains brain endothelial cell function via Tie2 signaling.
In: Nature Neuroscience, Vol. 29: pp. 325-336
[PDF, 35MB]
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.
| Item Type: | Journal article |
|---|---|
| EU Funded Grant Agreement Number: | 666881 |
| Faculties: | Medicine > Biomedical Center Medicine > Munich Cluster for Systems Neurology (SyNergy) Medicine > Institute for Stroke and Dementia Research (ISD) |
| Research Centers: | Graduate School of Systemic Neurosciences (GSN) |
| Subjects: | 600 Technology > 610 Medicine and health |
| URN: | urn:nbn:de:bvb:19-epub-131230-0 |
| ISSN: | 1097-6256 |
| Language: | English |
| Item ID: | 131230 |
| Date Deposited: | 20. Jan 2026 09:00 |
| Last Modified: | 18. Aug 2026 08:12 |
| DFG: | Gefördert durch die Deutsche Forschungsgemeinschaft (DFG) - 390857198 |
| DFG: | Gefördert durch die Deutsche Forschungsgemeinschaft (DFG) - 542519968 |
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