Chensee, Grace and Lee, Bob S.L. and Green, Immanuel D. and Tieng, Jessica and Song, Renhua and Pinello, Natalia and Lee, Quintin and Mehravar, Majid and Robinson, David A. and Wang, Mian and Kavurma, Mary M. and Yu, Jun and Wong, Justin J.L. and Liu, Renjing (2025) METTL14 promotes intimal hyperplasia through m6A-mediated control of vascular smooth muscle dedifferentiation genes. JCI Insight, 10 (10). ISSN 2379-3708
Full text not available from this repository.Abstract
Vascular smooth muscle cells (VSMCs) possess significant phenotypic plasticity, shifting between a contractile phenotype and a synthetic state for vascular repair/remodeling. Dysregulated VSMC transformation, marked by excessive proliferation and migration, primarily drives intimal hyperplasia. N6-methyladenosine (m6A), the most prevalent RNA modification in eukaryotes, plays a critical role in gene expression regulation; however, its impact on VSMC plasticity is not fully understood. We investigated the changes in m6A modification and its regulatory factors during VSMC phenotypic shifts and their influence on intimal hyperplasia. We demonstrate that METTL14, crucial for m6A deposition, significantly promoted VSMC dedifferentiation. METTL14 expression, initially negligible, was elevated in synthetic VSMC cultures, postinjury neointimal VSMCs, and human restenotic arteries. Reducing Mettl14 levels in mouse primary VSMCs decreased prosynthetic genes, suppressing their proliferation and migration. m6A-RIP-seq profiling showed key VSMC gene networks undergo altered m6A regulation in Mettl14-deficient cells. Mettl14 enhanced Klf4 and Serpine1 expression through increased m6A deposition. Local Mettl14 knockdown significantly curbed neointimal formation after arterial injury, and reducing Mettl14 in hyperplastic arteries halted further neointimal development. We show that Mettl14 is a pivotal regulator of VSMC dedifferentiation, influencing Klf4- and Serpine1-mediated phenotypic conversion. Inhibiting METTL14 is a viable strategy for preventing restenosis and halting restenotic occlusions.
| Item Type: | Article |
|---|---|
| Subjects: | R Medicine > R Medicine (General) |
| Depositing User: | Repository Administrator |
| Date Deposited: | 31 Oct 2025 04:32 |
| Last Modified: | 31 Oct 2025 04:32 |
| URI: | http://eprints.victorchang.edu.au/id/eprint/1707 |
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