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Understanding the pathogenesis of brain arteriovenous malformation: genetic variations, epigenetics, signaling pathways, and immune inflammation

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Abstract

Brain arteriovenous malformation (BAVM) is a rare but serious cerebrovascular disease whose pathogenesis has not been fully elucidated. Studies have found that epigenetic regulation, genetic variation and their signaling pathways, immune inflammation, may be the cause of BAVM the main reason. This review comprehensively analyzes the key pathways and inflammatory factors related to BAVMs, and explores their interplay with epigenetic regulation and genetics. Studies have found that epigenetic regulation such as DNA methylation, non-coding RNAs and m6A RNA modification can regulate endothelial cell proliferation, apoptosis, migration and damage repair of vascular malformations through different target gene pathways. Gene defects such as KRAS, ACVRL1 and EPHB4 lead to a disordered vascular environment, which may promote abnormal proliferation of blood vessels through ERK, NOTCH, mTOR, Wnt and other pathways. PDGF-B and PDGFR-β were responsible for the recruitment of vascular adventitial cells and smooth muscle cells in the extracellular matrix environment of blood vessels, and played an important role in the pathological process of BAVM. Recent single-cell sequencing data revealed the diversity of various cell types within BAVM, as well as the heterogeneous expression of vascular-associated antigens, while neutrophils, macrophages and cytokines such as IL-6, IL-1, TNF-α, and IL-17A in BAVM tissue were significantly increased. Currently, there are no specific drugs targeting BAVMs, and biomarkers for BAVM formation, bleeding, and recurrence are lacking clinically. Therefore, further studies on molecular biological mechanisms will help to gain insight into the pathogenesis of BAVM and develop potential therapeutic strategies.

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Funding

This study was supported by the grants from the Zhejiang Provincial Natural Science Foundation of China (LY22H090001), Ningbo Health Branding Subject Fund (PPXK2018-04), Ningbo Top Medical and Health Research Program (2022020304), Key Laboratory of Precision Medicine for Atherosclerotic Diseases of Zhejiang Province (2022E10026).

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  1. Shiyi Wang and Xinpeng Deng have contributed equally to this work and share the first authorship.

Authors and Affiliations

  1. Department of Neurology, The First Affiliated Hospital of Ningbo University, Ningbo, 315010, Zhejiang, China

    Shiyi Wang, Yuefei Wu & Jianhong Yang

  2. Department of Neurosurgery, The First Affiliated Hospital of Ningbo University, Ningbo, 315010, Zhejiang, China

    Xinpeng Deng, Yiwen Wu, Shengjun Zhou & Yi Huang

  3. Key Laboratory of Precision Medicine for Atherosclerotic Diseases of Zhejiang Province, Ningbo, 315010, Zhejiang, China

    Yi Huang

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Contributions

YH and JY contributed to the conception and design of the study. SW, XD, YW, YW and SZ organized the database. SW and XD wrote the first draft of the manuscript. YH reviewed and edited.

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Correspondence to Jianhong Yang or Yi Huang.

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Wang, S., Deng, X., Wu, Y. et al. Understanding the pathogenesis of brain arteriovenous malformation: genetic variations, epigenetics, signaling pathways, and immune inflammation. Hum. Genet. 142, 1633–1649 (2023). https://doi.org/10.1007/s00439-023-02605-6

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