Smooth Muscle Cell MAPK14 Promotes Vascular Calcification During Hyperlipidemic Aging.

Vascular calcification is a hallmark of vascular aging that is accelerated by hyperlipidemia and contributes to adverse cardiovascular outcomes. Although vascular smooth muscle cells (VSMCs) are key mediators of vascular calcification, the signaling pathways linking aging-associated stress to osteogenic remodeling remain incompletely understood. To define the role of MAPK14 (p38α) in vascular aging, we integrated bulk RNA sequencing of young and aged mouse aortas with published single-nucleus RNA sequencing data from VSMC-specific Mapk14 knockout (KO) mice. Bulk RNA-seq identified age-associated activation of extracellular matrix remodeling, calcification, inflammatory, and senescence-associated gene programs, accompanied by increased p38 MAPK signaling. Single-nucleus RNA-seq further demonstrated that Mapk14 KO attenuated proliferative, inflammatory, fibrotic, and ossification-associated gene modules in VSMCs. Consistent with these transcriptomic findings, RUNX2 expression was markedly increased in aged aortas, whereas aged Mapk14 KO mice exhibited reduced RUNX2 expression together with attenuated vascular calcification, fibrosis, and inflammatory cell infiltration compared with wild-type controls. Collectively, these results identify VSMC MAPK14 as an important regulator of vascular calcification during hyperlipidemic aging and demonstrate that MAPK14 deficiency is associated with reduced RUNX2 expression and attenuated fibro-inflammatory vascular remodeling. These findings support MAPK14 as a potential therapeutic target for limiting vascular calcification and associated pathological remodeling during aging.