Authors
Ganglei Li, Mingjian Liu, Hongfei Zhang, Sichen Li, Yingjun Liu, Tonglin Pan, Shiyu Shen, Zongze Li, Wei Zhu
Published in
Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism. Pages 271678X261479444. Aug 11, 2026. Epub Aug 11, 2026.
Abstract
Brain arteriovenous malformations (bAVMs) are high-risk vascular lesions prone to intracranial hemorrhage, with unclear upstream regulatory mechanisms. We integrated 5-methylcytosine (m⁵C) RNA methylation sequencing and transcriptomics in ruptured and unruptured bAVMs to identify differentially methylated non-coding RNAs. Functional validation was performed in human tissues, HUVECs, and zebrafish models. m⁵C profiling revealed global methylation remodeling in ruptured bAVMs, with enrichment of EndMT and Wnt/β-catenin pathways. USP2-AS1 emerged as a key lncRNA showing increased methylation and expression, predominantly in endothelial cells. In HUVECs, USP2-AS1 promoted EndMT-like changes and migration, while its knockdown had opposite effects. NSUN6 was identified as the primary methyltransferase mediating m⁵C modification of USP2-AS1. NSUN6-driven methylation enhanced endothelial plasticity in vitro and induced vascular abnormalities and hemorrhage in zebrafish. Mechanistically, USP2-AS1 activated Wnt/β-catenin signaling, which was essential for these effects and reversible by pathway inhibition. These findings identify a NSUN6-USP2-AS1-Wnt/β-catenin axis that drives endothelial dysfunction and bAVM rupture, suggesting potential therapeutic targets for vascular stabilization.
PMID:
42581416
Bibliographic data and abstract were imported from PubMed on 12 Aug 2026.
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