The NRF2/ID2 Axis in Vascular Smooth Muscle Cells: Novel Insights into the Interplay between Vascular Calcification and Aging

Vascular calcification (VC) increases with age and markedly exacerbates the risk of cardiovascular morbidity and mortality. However, effective pharmaceutical interventions are lacking and the molecular mechanisms linking aging to VC remain elusive. This study explored the role of nuclear factor erythroid 2-related factor 2 (NRF2) in age-associated VC, specifically focusing on vascular smooth muscle cell (VSMC) senescence. Using a chronologically aging mouse model, we noted a significant decline in the expression of NRF2 in the aged mice aortas, coinciding with increased VC. Administering NRF2 activators effectively reduced calcification. By establishing adenine-and vitamin D-induced VC models in VSMC-specific Nrf2 knockout (Nrf2^SMCKO) mice, there was an increase in VC with increased VSMC senescence. Aortic rings and primary VSMCs from Nrf2^SMCKO mice also showed increased VC under high-phosphate conditions. Furthermore, Nrf2 overexpression inhibited VSMC calcification with decreased VSMC senescence and an osteogenic phenotype, whereas Nrf2 silencing aggravated calcification. Transcriptome RNA-seq analysis of the aortas from Nrf2^SMCKO and control mice revealed that inhibitor of DNA binding 2 (Id2) is a core downstream gene of NRF2. Id2 overexpression alleviated NRF2 knockdown-induced VC and VSMC senescence, while silencing Id2 negated the protective effects of NRF2. Moreover, results of a dual luciferase reporter assay indicated that NRF2 promotes the transcriptional activity of the Id2 gene promoter region. This study emphasizes the critical role of age-related NRF2 dysfunction in the nexus between VSMC senescence and VC. The NRF2-ID2 axis in VSMCs has been proposed as a promising therapeutic target for reducing VC and mitigating age-related cardiovascular diseases.