Noncoding navigators of vascular smooth muscle cells: lncRNAs at the interface of vascular plasticity and therapeutic...

Vascular smooth muscle cell (VSMC) plasticity underlies both adaptive and maladaptive vascular remodelling in cardiovascular disease. Contractile VSMCs maintain vascular tone and structural integrity, whereas pathological stimuli, such as inflammation, oxidative stress, hyperglycaemia, and mechanical injury induce phenotypic switching toward synthetic, proliferative, and osteogenic states. Emerging evidence implicates long non-coding RNAs (lncRNAs) as central regulators of these phenotypic transitions. Nuclear lncRNAs, including ANRIL, modulate chromatin architecture and recruit histone-modifying complexes to drive proliferation and repress contractile gene expression, while CARMN stabilizes SRF-Myocardin transcriptional complexes to preserve contractile identity. Cytoplasmic lncRNAs, such as SMILR, HIF1A-AS2, and PVT1, act as competing endogenous RNAs to sequester microRNAs, reinforcing pro-proliferative and pro-migratory programs. In disease contexts, dysregulated lncRNAs contribute to atherosclerosis, pulmonary arterial hypertension (PAH), restenosis, and vascular calcification. For example, MEG3, CASC2, MALAT1 and NEAT1 orchestrate hyperproliferation and apoptosis resistance in pulmonary artery smooth muscle cells, driving PAH progression, whereas H19, DANCR, and GAS5 regulate WNT/β-catenin, BMP, and NOTCH pathways to mediate VSMC osteogenic trans-differentiation in diabetes and chronic kidney disease. Translationally, circulating lncRNAs such as SMILR and ANRIL serve as potential biomarkers of vascular pathology, and preclinical studies targeting CARMN, MALAT1, and CASC2 demonstrate efficacy in modulating pathological remodelling. Collectively, lncRNAs integrate transcriptional, epigenetic, and post-transcriptional networks to govern VSMC phenotype and represent promising therapeutic targets for precision vascular medicine.