Inhibition of endothelial histone deacetylase 2 shifts endothelial-mesenchymal transitions in cerebral arteriovenous malformation models
Yan Zhao, Xiuju Wu, Yang Yang, Li Zhang, Xinjiang Cai, Sydney Chen, Abigail Vera, Jaden Ji, Kristina I. Boström, Yucheng Yao
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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Research Article Vascular biology

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

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 8

Alterations in HDAC2 and EZH1 cause changes in H4K8ac and H3K27me3 in the regulation of endothelial and mesenchymal differentiation.

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Alterations in HDAC2 and EZH1 cause changes in H4K8ac and H3K27me3 in th...
(A) Expression of Hdac2 and Ezh1 in MGP CRISPR cells and control HBMECs shown by real-time PCR (n = 6). (B) Abundance of H4K8ac and H3K27me3 in MGP CRISPR cells and control HBMECs shown by immunoblotting with densitometry. H3 and H4 were used as loading controls. (C) Expression of HDAC2, VE-cadherin, SNAI1, EZH1, JAGGED1, JAGGED2, and SOX2 and abundance of H4K8ac and H3K27me3 in MGP CRISPR cells after transfection with HDAC2 siRNA or infection with CMV-Ezh1 lentivirus or a combination of both, as shown by immunoblotting with densitometry. CMV, cytomegalovirus promoter. β-Actin, H3, and H4 were used as loading controls. (D) Expression of Snai1 and Cdh2 in HBMECs or MGP CRISPR cells after overexpression or depletion of Snai1 and Cdh2 (n = 6). (E) Expression of lumen-associated genes in HBMECs or MGP CRISPR cells after overexpression or depletion of Cdh2 (n = 6). (F) Immunoblotting with densitometry after coimmunoprecipitation with anti-SNAI1, anti-SOX2, or anti-JMJD5 antibodies in HBMECs or MGP CRISPR cells. Data represented in A and E were analyzed for statistical significance using unpaired, 2-tailed Student’s t test. Data represented in D were analyzed for statistical significance using ANOVA with post hoc Tukey’s 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 < 0.0001.