Elevated endothelial Sox2 causes lumen disruption and cerebral arteriovenous malformations
Jiayi Yao, Xiuju Wu, Daoqin Zhang, Lumin Wang, Li Zhang, Eric X. Reynolds, Carlos Hernandez, Kristina I. Boström, Yucheng Yao
Jiayi Yao, Xiuju Wu, Daoqin Zhang, Lumin Wang, Li Zhang, Eric X. Reynolds, Carlos Hernandez, Kristina I. Boström, Yucheng Yao
View: Text | PDF
Research Article Vascular biology

Elevated endothelial Sox2 causes lumen disruption and cerebral arteriovenous malformations

Abstract

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.

Authors

Jiayi Yao, Xiuju Wu, Daoqin Zhang, Lumin Wang, Li Zhang, Eric X. Reynolds, Carlos Hernandez, Kristina I. Boström, Yucheng Yao

×

Figure 4

Excess Sox2 alters the transcriptional landscape of Mgp–/– cerebral ECs and activates JMJD5.

Options: View larger image (or click on image) Download as PowerPoint
Excess Sox2 alters the transcriptional landscape of Mgp–/– cerebral ECs ...
(A) Heatmap showing the densities at Sox2-binding sites in cerebral ECs obtained from ChIP-Seq data. Blue indicates a low level and red a high level. (B) Heatmap showing occupancy of H3K27m3 and H3K4m3 in cerebral ECs, as obtained from ChIP-Seq data. Blue indicates a low level and red a high level. (C) Profile of occupancy of H3K27m3 and H3K4m3 around Sox2-binding sites ± 3 kb. (D) Gene ontology analysis showing the genes with increased Sox2 binding and changes of bivalent marks in regulatory regions in cerebral ECs. (E) Plots of Sox2, H3K4m3, and H3K27m3 at JMJD5 loci in Mgp+/+ and Mgp–/– cerebral ECs. (F and G) Expression of JMJD5 in Mgp+/+ and Mgp–/– cerebral ECs as shown by (F) immunostaining and (G) immunoblotting (n = 5). Scale bars: 100 μm. (H) Suppression of Sox2 abolished the increase of JMJD5 in Mgp–/– cerebral ECs, as detected by real-time PCR (n = 5) and analyzed by 1-way ANOVA with Tukey’s multiple comparisons test. Data are shown by box and whisker plots. The bounds of the boxes represent upper and lower quartiles. The lines in the boxes represent the median, and the whiskers represent the maximum and minimal values. ***P < 0.001.