Epigenetics enters the stage in vascular malformations
Salim Abdelilah-Seyfried
Salim Abdelilah-Seyfried
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Commentary

Epigenetics enters the stage in vascular malformations

Abstract

Cerebral arteriovenous malformations represent the most common form of vascular malformations and can cause recurrent bleeding and hemorrhagic stroke. The current issue of the JCI features an article by Zhao et al. describing a mouse model of cerebral arteriovenous malformations. Endothelial cells lacking matrix Gla protein, a BMP inhibitor, underwent epigenetic changes characteristic of an endothelial-to-mesenchymal fate transition. The authors uncovered a two-step process for this transition controlled by the epigenetic regulator histone deacetylase 2 (HDAC2), which controls endothelial cell differentiation, and by enhancer of zeste homolog 1 (EZH1), which suppressed mesenchymal fate. This discovery provides a promising entry point for preventive pharmacological interventions.

Authors

Salim Abdelilah-Seyfried

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Figure 1

Epigenetic changes causing an EndMT in cerebral AVMs reveal a targetable pathway.

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Epigenetic changes causing an EndMT in cerebral AVMs reveal a targetable...
(A) The activation of mesenchymal genes and JAGGED1/2 has been implicated in the formation of cerebral AVMs. Strong activation of HDAC2 results in transition from the endothelial cell state to a mesenchymal fate (EndMT) and activation of JAGGED1/2. (B) In healthy conditions, EZH1 suppresses the activation of mesenchymal genes and JAGGED1/2. MGP activity suppresses signaling by BMP6/ALK3, preventing the activation of HDAC2. This suppression ensures a two-tier molecular regulatory mechanism in preventing EndMT and cerebral AVMs: (i) suppression of HDAC2 alleviates the negative control of genes involved in endothelial differentiation and of Ezh1; (ii) EZH1 methylates genes associated with mesenchymal fate, thus making them less accessible. These pathways offer an entry point for preventive pharmacological interventions in cerebral AVMs that are characterized by a strong activation of HDAC2. Zhao et al. demonstrate an effective treatment for cerebral AVMs using the HDAC2 inhibitor HC toxin in a mouse model.