Mechanotransduction through oxidative stress upregulates circLyst to drive vascular remodeling in hypertensive humans and rodents.

Aberrant cyclic stretch serves as a critical driver of vascular remodeling in hypertension, yet the underlying molecular mechanisms remain largely unknown. Here, we studied the role of a novel circRNA, termed circ_2465 (circLyst), in vascular remodeling in both human and rodent samples under high cyclic stretch. Next-generation sequencing data revealed that 165 circRNAs were differentially expressed in the thoracic aortas of spontaneously hypertensive rats (SHRs) compared with normotensive Wistar-Kyoto rats (WKYs), of which 60 circRNAs were significantly upregulated while 105 circRNAs were significantly downregulated. CircLyst, verified as a novel circRNA by ribonuclease R (RNase R) digestion and Actinomycin D assays, was induced in the thoracic aortas of SHRs and stably located in the cytoplasm as detected by fluorescence in situ hybridization (FISH). This elevation was confirmed in hypertensive patients and was recapitulated in vascular smooth muscle cells (VSMCs) exposed to high cyclic stretch in vitro. Mechanistically, oxidative stress, mediated by NADPH oxidases NOX1 and NOX4, induced circLyst expression. CircLyst then functioned as a sponge for miR-298-5p, derepressing its target gene Col23a1, thereby promoting VSMC proliferation and migration-key events in vascular remodeling. Importantly, both systemic and VSMC-specific targeting of circLyst attenuated pathological remodeling and blunted hypertension in animal models. Collectively, our findings establish the oxidative-stress-driven circLyst/miR-298-5p/Col23a1 axis as a critical regulator of vascular remodeling and highlight circLyst as a potential therapeutic target for hypertensive vascular disease.