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
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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

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Figure 3

Excess Sox2 alters EC differentiation to cause lumen disorder in the cerebral vasculature of Mgp–/– mice.

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Excess Sox2 alters EC differentiation to cause lumen disorder in the cer...
(A) The population of CD31-positive ECs isolated from the cerebra of Mgp+/+ and Mgp–/– mice. (B and C) Expression of mesenchymal and stem cell markers (B) and endothelial markers (C) in different cell populations isolated from the cerebra of Mgp+/+ and Mgp–/– mice (n = 5). (D and E) Correlation between increased Sox2 and N-cadherin and increased frequency of vessels with radii ranging from 20 to 50 μm (n = 15). (F) Flow cytometric analysis of cerebral ECs isolated from Mgp+/+ and Mgp–/– mice (n = 3). (G) High expression of the lumen-associated genes Rasip1, Par3, and β1-integrin in Sox2 and N-cadherin double-positive cerebral ECs isolated from Mgp–/– mice (n = 5). Mgp+/+ mice were used as controls. (H and I) Decreased expression of mesenchymal markers N-cadherin and c-kit (H) and lumen-associated genes Par3 and Rasip1 (I) in cerebral ECs of Cdh5CreSox2fl/WTMgp–/– mice, as detected by real-time PCR (n = 6). Data shown in B, H, and I were analyzed by 1-way ANOVA with Tukey’s multiple comparisons test. Data shown in C and G were analyzed by Student’s t 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 < 0.01; ***P < 0.001.