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 1

EndMTs correlate with lumen disorder in human cerebral AVMs.

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EndMTs correlate with lumen disorder in human cerebral AVMs. (A) The exp...
(A) The expression of Sox2 and N-cadherin (N-cad) in lesions of cerebral AVMs (CAVM) was examined by immunofluorescence staining (n = 5). CD31 (green) was used as a marker for the endothelium. Normal cerebral vessels were used as controls. HTB133 cells were used as positive controls for the anti–N-cadherin antibodies (bottom). Scale bars: 100 μm. (B) Flow cytometric analysis of expression of N-cadherin in CD31-positive cells isolated by fluorescence-activated cell sorting (n = 3). (C and D) Expression of endothelial and mesenchymal markers in lesions of cerebral AVMs, as shown by real-time PCR (n = 5). SMA, smooth muscle actin; VE-cad, VE-cadherin. Data 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 < 0.001. (E and F) Correlation between the fold increase in expression of the lumen-associated gene Par3 and (E) Sox2 and (F) N-cadherin (n = 10). (G) Schematic diagram: ECs with EndMTs cause lumen disorder.