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 2

Suppression of Sox2 reduces cerebral AVMs.

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Suppression of Sox2 reduces cerebral AVMs. (A) Time-course expression of...
(A) Time-course expression of MGP in cerebral ECs of WT mice (n = 6). (B) Time-course expression of Sox2 in cerebral ECs of WT (Mgp+/+) and Mgp–/– mice (n = 6). (C and D) Decreased expression of Sox2 in cerebral ECs of Cdh5CreSox2fl/WTMgp–/– mice detected by real-time (C) PCR and (D) immunostaining (n = 5). CD31 (green) was used as an endothelial marker. Scale bars: 100 μm. Asterisk indicates arteriovenous shunt with enlarged lumen. (E) μCT images of the cerebral vasculature in mice with colors reflecting the vessel radii (n = 3). Scale bar: 1 mm. (F) Frequency of vessels with different radii in the cerebrum of mice detected by μCT imaging (n = 3). (G) Arteriovenous shunting examined by UV-fluorescent microsphere passage in lungs and kidneys (n = 8). BF, bright field. (H) Frequency of capillaries ranging from 5 to 10 μm and small arteries ranging from 20 to 25 μm in the cerebrum of mice examined by μCT imaging (n = 3). (I) Expression of VEGF in brain, as determined by real-time PCR (n = 5). Data shown in C, H, and I were 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.