TWEAK Receptor Promotes Vascular Remodeling in Hypertension by Activating Autophagy

Background Vascular remodeling, a pathological hallmark of hypertensive target‐organ damage, is critically modulated by autophagy. Given the emerging role of TWEAK (tumor necrosis factor–like weak inducer of apoptosis)/TWEAK receptor (TWEAKR) signaling in cardiovascular pathogenesis, this study investigates the relationship between TWEAK/TWEAKR and autophagy in hypertension‐associated vascular remodeling. Methods Peripheral blood TWEAK levels were measured in patients with hypertension and spontaneously hypertensive rats. To elucidate the role of TWEAKR in autophagy and vascular remodeling, lentivirus‐mediated knockdown of TWEAKR was performed. A multiple strategy integrating western blot, reverse transcription polymerase chain reaction, coimmunoprecipitation, liquid chromatography–mass spectrometry, RNA sequencing, immunohistochemistry and immunofluorescence staining, and transmission electron microscopy was used. Experimental validation was conducted in vitro using rat aortic vascular smooth muscle cells and in vivo using spontaneously hypertensive rats and their normotensive controls, Wistar–Kyoto rats. Results Serum TWEAK levels were unchanged in patients with hypertension and spontaneously hypertensive rats compared with controls, whereas TWEAKR expression was elevated. TWEAKR knockdown attenuated vascular remodeling and suppressed abnormal autophagy, independent of blood pressure or heart rate. Specifically, TWEAKR knockdown inhibited angiotensin II–induced autophagy, while TWEAKR overexpression enhanced this process. Furthermore, TWEAKR knockdown suppressed excessive proliferation, migration, and phenotypic switch of rat aortic vascular smooth muscle cells. Mechanistically, TWEAKR regulated autophagy by inhibiting TRIM21 (tripartite motif containing 21) expression via the ERK1/2 (extracellular signal‐regulated kinase 1/2) pathway. Reduced TRIM21 decreased eIF4A3 (eukaryotic translation initiation factor 4A3) ubiquitination, promoting its nuclear translocation and inducing autophagy, thereby exacerbating vascular remodeling. TRIM21 interacted with eIF4A3 via its coiled‐coil domain, primarily catalyzing K63‐linked polyubiquitination. Notably, vascular remodeling was attenuated by TWEAKR knockdown but not by dual knockdown of TWEAKR and TRIM21. Conclusions TWEAKR regulates TRIM21 levels through the ERK1/2 pathway, modulating eIF4A3 subcellular localization and autophagy, thereby influencing hypertension‐associated vascular remodeling. These findings highlight TWEAKR as a potential therapeutic target for hypertension‐induced vascular pathology.