Epitranscriptomic regulation of endothelial plasticity under hemodynamic forces: insights from the KLF2/4-METTL3-H19...

Hemodynamic shear stress is a fundamental biomechanical cue that shapes endothelial phenotypes and contributes to vascular diseases. Although flow-responsive transcription factors such as KLF2 and KLF4 are well recognized, how mechanical forces converge on epitranscriptomic mechanisms to regulate RNA fate remains incompletely understood. Emerging evidence identifies N⁶-methyladenosine (m⁶A) modification as a dynamic regulator of non-coding RNA stability and endothelial function, yet its integration into shear-dependent remodeling has not been systematically explored. This review synthesizes current evidence on the interplay between shear stress and the m⁶A regulatory machinery and discusses how epitranscriptomic modulation of coding and non-coding RNAs may contribute to endothelial plasticity. Within this broader framework, the KLF2/4-METTL3-H19 pathway is presented as a representative mechanistic module illustrating how flow-responsive transcriptional programs may intersect with RNA methylation processes and reader-mediated transcript regulation. The potential implications of such interactions for endothelial-to-mesenchymal transition, barrier integrity, angiogenesis, and vascular diseases-including atherosclerosis, pulmonary arterial hypertension, and diabetic microangiopathy-are discussed. This integrated perspective highlights the emerging role of mechano-epitranscriptomic crosstalk in vascular biology and identifies directions for future investigation.