First Author | Yao J | Year | 2019 |
Journal | J Clin Invest | Volume | 129 |
Issue | 8 | Pages | 3121-3133 |
PubMed ID | 31232700 | Mgi Jnum | J:286134 |
Mgi Id | MGI:6400152 | Doi | 10.1172/JCI125965 |
Citation | Yao J, et al. (2019) Elevated endothelial Sox2 causes lumen disruption and cerebral arteriovenous malformations. J Clin Invest 129(8):3121-3133 |
abstractText | 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 beta-adrenergic antagonist pronethalol as an inhibitor of Sox2 expression. Treatment with pronethalol stabilized endothelial differentiation and lumen formation, which limited the cerebral AVMs. |