Elevated endothelial Sox2 causes lumen disruption and cerebral arteriovenous malformations
Jiayi Yao, … , Kristina I. Boström, Yucheng Yao
Jiayi Yao, … , Kristina I. Boström, Yucheng Yao
Published June 24, 2019
Citation Information: J Clin Invest. 2019;129(8):3121-3133. https://doi.org/10.1172/JCI125965.
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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 7

Pronethalol improves cerebral AVMs in Mgp–/– mice.

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Pronethalol improves cerebral AVMs in Mgp–/– mice. (A) Pronethalol decre...
(A) Pronethalol decreases arteriovenous shunting in Mgp–/– mice, as demonstrated by UV-fluorescent microsphere injections (n = 5). Scale bars: 1 mm. (B) Relative density of retained fluorescent microspheres in the brains of Mgp+/+ and Mgp–/– mice after treatment with pronethalol (n = 5). (C) μCT images of the cerebral vasculature with colors reflecting the vessel radii from Mgp+/+ and Mgp–/– mice with or without treatment with pronethalol (n = 3). Scale bars: 1 mm. (D) Frequency of vessels with different radii in the cerebra of mice detected by μCT imaging (n = 3). (E) Expression of Sox2, JMJD5, N-cadherin, and Par3 in cerebral ECs isolated from Mgp+/+ and Mgp–/– mice that were treated with pronethalol (n = 6). (F and G) Arteriovenous shunting examined by UV-fluorescent microsphere passage in lungs and kidneys (n = 4). Data shown in B and E 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.