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Inhibition of endothelial histone deacetylase 2 shifts endothelial-mesenchymal transitions in cerebral arteriovenous malformation models
Yan Zhao, … , Kristina I. Boström, Yucheng Yao
Yan Zhao, … , Kristina I. Boström, Yucheng Yao
Published May 23, 2024
Citation Information: J Clin Invest. 2024;134(15):e176758. https://doi.org/10.1172/JCI176758.
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Research Article Vascular biology

Inhibition of endothelial histone deacetylase 2 shifts endothelial-mesenchymal transitions in cerebral arteriovenous malformation models

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Abstract

Cerebral arteriovenous malformations (AVMs) are the most common vascular malformations worldwide and the leading cause of hemorrhagic strokes that may result in crippling neurological deficits. Here, using recently generated mouse models, we uncovered that cerebral endothelial cells (ECs) acquired mesenchymal markers and caused vascular malformations. Interestingly, we found that limiting endothelial histone deacetylase 2 (HDAC2) prevented cerebral ECs from undergoing mesenchymal differentiation and reduced cerebral AVMs. We found that endothelial expression of HDAC2 and enhancer of zeste homolog 1 (EZH1) was altered in cerebral AVMs. These alterations changed the abundance of H4K8ac and H3K27me in the genes regulating endothelial and mesenchymal differentiation, which caused the ECs to acquire mesenchymal characteristics and form AVMs. This investigation demonstrated that the induction of HDAC2 altered specific histone modifications, which resulted in mesenchymal characteristics in the ECs and cerebral AVMs. The results provide insight into the epigenetic impact on AVMs.

Authors

Yan Zhao, Xiuju Wu, Yang Yang, Li Zhang, Xinjiang Cai, Sydney Chen, Abigail Vera, Jaden Ji, Kristina I. Boström, Yucheng Yao

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Figure 1

Endothelial-specific deletion of Mgp causes cerebral AVMs.

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Endothelial-specific deletion of Mgp causes cerebral AVMs.
(A) Time-cour...
(A) Time-course expression of Mgp in CD31+CD45– cerebral ECs isolated from VE-cadherincre/ERT2Mgpfl/fl mice treated with or without tamoxifen (n = 6). (B) Time course for frequency of brain vessels with different radii in VE-cadherincre/ERT2Mgpfl/fl mice treated with or without tamoxifen, as determined by micro-CT imaging (n = 6). (C) Micro-CT imaging of brain vasculature in VE-cadherincre/ERT2Mgpfl/fl mice on days 12 and 15 after treatment with tamoxifen. Day 0 represents the control treatment. Arrowheads represent A-V shunts. A, artery. V, vein. Scale bars: 1 mm. (D) Highlight of A-V shunts on day 15 after treatment with tamoxifen compared with control. Scale bars: 0.5 mm. (E) Average radii of vessels in corresponding areas in the control group and tamoxifen-injected group (n = 6). (F and G) A-V shunting as demonstrated by fluorescent microsphere passage with quantitation of retained fluorescent microspheres in the brains of VE-cadherincre/ERT2Mgpfl/fl mice from day 0 to 15 after treatment with tamoxifen (n = 4). BF, bright field. Scale bars: 1 mm. (H) Schematic diagram of fluorescent microsphere passage. Data represented in A, B, and G were analyzed for statistical significance by ANOVA with post hoc Tukey’s test. Data represented in E were analyzed for statistical significance by unpaired, 2-tailed Student’s t test. The bounds of the boxes show upper and lower quartiles with data points. The lines in the boxes show the medians. Error bars represent maximal and minimal values. **P < 0.001; ***P < 0.0001.

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ISSN: 0021-9738 (print), 1558-8238 (online)

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