Scholarlink

<p>Cerebral small vessel disease (SVD) is a common chronic cerebrovascular disorder with poorly understood pathomechanisms. Genetic studies have identified <i>FOXF2</i> 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 <i>FOXF2</i> 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.</p>

错误：搜索内容不能为空，请输入英文关键词
错误：关键词超出字数限制，请精简
高级检索

The stroke risk gene Foxf2 maintains brain endothelial cell function via Tie2 signaling

  • 期刊论文

  • 出版模式：

    开放获取

  • 发表日期：

    2025年12月15日

查看全文
  • Katalin Todorov-Völgyi,
  • Judit González-Gallego,
  • Stephan A. Müller,
  • Mihail Ivilinov Todorov,
  • Fatma Burcu Seker,
  • Simon Frerich,
  • Filippo M. Cernilogar,
  • Luise Schröger,
  • Rainer Malik,
  • Jiayu Cao,
  • Gemma Llovera,
  • Stefan Roth,
  • Ulrike Schillinger,
  • Martina Schifferer,
  • Azadeh Reyahi,
  • Dennis Crusius,
  • Liliana D. Pedro,
  • Mikael Simons,
  • Peter Carlsson,
  • Ali Ertürk,
  • Arthur Liesz,
  • Gunnar Schotta,
  • Nikolaus Plesnila,
  • Stefan F. Lichtenthaler,
  • Dominik Paquet,
  • Martin Dichgans

摘要

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.