Non-Coding RNAs in Obesity-Driven Vascular Dysfunction: Mechanisms, EndMT, and Translational Opportunities

Obesity is a systemic vascular disease characterized by the convergence of metabolic excess and adipose dysfunction, leading to endothelial injury and plasticity. Beyond hemodynamic stress, chronic nutritional and inflammatory stimuli trigger oxidative and pro-thromboinflammatory pathways, reduce nitric oxide bioavailability, and promote endothelial-to-mesenchymal transition (EndMT). This process contributes to fibrotic remodeling, plaque vulnerability, arterial stiffening, and microvascular rarefaction. Non-coding RNAs (ncRNAs)-microRNAs (miRNAs), long ncRNAs (lncRNAs), and circular RNAs (circRNAs)-play pivotal roles as regulators within the vascular wall and across tissues via extracellular vesicles (EVs) derived from adipose tissue and perivascular fat. We synthesize evidence demonstrating that ncRNAs integrate TGF-β/Smad, NF-κB, HIF-1α, and Wnt/β-catenin signaling pathways with the endothelial metabolic state, including the epigenetic regulation of EndMT linked to fatty acid oxidation. Single-cell and lineage-tracing studies identify nascent EndMT subpopulations in obese tissues, while in vitro models reveal cytokine and lipotoxic triggers that shift ncRNA networks, stabilizing mesenchymal programs. Translationally, circulating and EV-associated ncRNAs mirror adiposity, dyslipidemia, insulin resistance, and endothelial dysfunction, improving with weight loss. This underscores their potential as dynamic biomarkers for patient stratification, particularly when integrated with vascular imaging and functional assays. Furthermore, we discuss therapeutic strategies such as miRNA antagomirs, lncRNA gapmers, and circRNA inhibitors, addressing the critical challenge of endothelium-targeted delivery through approaches like ligand-directed nanoparticles, endothelial-tropic liposomes, and engineered EVs. This review positions obesity-associated vascular disease as an ncRNA-driven network disorder and outlines pathways toward precision diagnostics and RNA-based interventions.