Elevated endothelial Sox2 causes lumen disruption and cerebral arteriovenous malformations
| Autor: | Xiuju Wu, Daoqin Zhang, Yucheng Yao, Kristina I. Boström, Eric X. Reynolds, Lumin Wang, Li Zhang, Jiayi Yao, Carlos X. Hernández |
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| Rok vydání: | 2018 |
| Předmět: |
0301 basic medicine
Intracranial Arteriovenous Malformations Pathology medicine.medical_specialty Jumonji Domain-Containing Histone Demethylases Transcription Genetic Lumen (anatomy) 03 medical and health sciences Mice 0302 clinical medicine SOX2 medicine Animals Humans Epigenetics Histone Demethylases Mice Knockout business.industry SOXB1 Transcription Factors Antagonist Endothelial Cells Arteriovenous malformation Cell Differentiation General Medicine Pronethalol medicine.disease Endothelial differentiation Cerebral arteriovenous malformations 030104 developmental biology Gene Expression Regulation Ethanolamines 030220 oncology & carcinogenesis business medicine.drug Research Article |
| Zdroj: | The Journal of clinical investigation. 129(8) |
| ISSN: | 1558-8238 |
| Popis: | Lumen integrity in vascularization requires fully differentiated endothelial cells (ECs). Here, we report that endothelial-mesenchymal transitions (EndMTs) emerged in ECs of cerebral arteriovenous malformation (AVMs) and caused disruption of the lumen or lumen disorder. We show that excessive Sry-box 2 (Sox2) signaling was responsible for the EndMTs in cerebral AVMs. EC-specific suppression of Sox2 normalized endothelial differentiation and lumen formation and improved the cerebral AVMs. Epigenetic studies showed that induction of Sox2 altered the cerebral-endothelial transcriptional landscape and identified jumonji domain-containing protein 5 (JMJD5) as a direct target of Sox2. Sox2 interacted with JMJD5 to induce EndMTs in cerebral ECs. Furthermore, we utilized a high-throughput system to identify the β-adrenergic antagonist pronethalol as an inhibitor of Sox2 expression. Treatment with pronethalol stabilized endothelial differentiation and lumen formation, which limited the cerebral AVMs. |
| Databáze: | OpenAIRE |
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