TY - JOUR AU - Yao, Jiayi AU - Wu, Xiuju AU - Zhang, Daoqin AU - Wang, Lumin AU - Zhang, Li AU - Reynolds, Eric X. AU - Hernandez, Carlos AU - Boström, Kristina I. AU - Yao, Yucheng T1 - Elevated endothelial Sox2 causes lumen disruption and cerebral arteriovenous malformations PY - 2019/08/01/ AB - 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. JF - The Journal of Clinical Investigation JA - J Clin Invest SN - 0021-9738 DO - 10.1172/JCI125965 VL - 129 IS - 8 UR - https://doi.org/10.1172/JCI125965 SP - 3121 EP - 3133 PB - The American Society for Clinical Investigation ER -