Epigenetic leash on the epitranscriptome: unveiling a novel regulatory axis in vascular smooth muscle contractility

This editorial refers to ‘YY1 regulates vascular resistance and blood pressure dynamics through epigenetic control of m6A RNA modifications in vascular smooth muscle cells’, by W. Ye et al., https://doi.org/10.1093/cvr/cvaf136. Vascular smooth muscle cell (VSMC) contractility is critically important for blood pressure regulation.1 Elevated VSMC contractility contributes to hypertension pathogenesis, while impaired contractility causing hypotension has recently been linked to aortic aneurysm formation.2 Therefore, elucidating the regulatory mechanisms underlying VSMC contraction is critical for understanding vascular homeostasis maintenance and the pathogenesis of related vascular diseases. N⁶-methyladenosine (m⁶A) represents the most prevalent epitranscriptional RNA modification in eukaryotes.3 The level of m⁶A modification is dynamically regulated by the balance between methylation and demethylation processes. Methyltransferase-like 3 (METTL3), the core catalytic subunit, combines with METTL14, WTAP, and other regulatory subunits to form the m⁶A methyltransferase complex (the ‘writer’), which catalyses m⁶A RNA methylation. Although METTL3-mediated m⁶A modification has been extensively reported to regulate VSMC phenotypic switching into pro-inflammatory, macrophage-like, proliferative, and migratory phenotypes, thereby facilitating neointimal formation and atherosclerosis,4–6 its potential role in VSMC contraction remained unexplored. Furthermore, METTL3 expression is up-regulated in VSMCs under various pathogenic stimuli (e.g. PDGF-BB and hyperlipidaemia),4,6 yet its regulatory mechanisms were largely unknown. The study by Ye et al. demonstrates that METTL3-mediated m⁶A modification plays a critical role in regulating VSMC contraction and reveals that epigenetic modulation involving the transcription factor Yin Yang 1 (YY1) promotes METTL3 expression, thereby controlling VSMC contractility.7 This work uncovers a profound and previously unrecognized regulatory layer: the epigenetic modulation of the VSMC epitranscriptome. This paradigm fundamentally shifts our understanding of vascular physiology by highlighting how epigenetic machinery directly orchestrates epitranscriptomic landscapes to control cellular function.