Mechanisms of vascular calcification: cellular phenotype switching drives matrix remodeling and mineralized...

Vascular calcification (VC), a prominent clinical characteristic of cardiovascular diseases, is intricately linked to chronic renal disease, diabetes, atherosclerosis, and other conditions, markedly increasing the risk of cardiovascular events. Traditionally perceived as a passive accumulation due to calcium-phosphate imbalance, recent findings now depict vascular calcification (VC) as an active mineralization process directed by vascular smooth muscle cells (VSMCs). This review seeks to elucidate the crucial role of VSMC phenotypic switching: Under the combined effects of metabolic disturbances (calcium-phosphate dysregulation, glucolipotoxicity), oxidative stress, and chronic inflammation, VSMCs shift from a contractile phenotype to an osteogenic/chondrogenic-like state. This transformation facilitates the establishment of a self-reinforcing mineralized microenvironment through matrix metalloproteinase (MMP)-mediated degradation of the extracellular matrix (ECM), release of matrix vesicles (MVs), and activation of pro-mineralization signal pathways (e.g., Wnt/β-catenin, BMP/SMAD). Additionally, endothelial-mesenchymal transition (EndoMT), macrophage polarization (M1/M2 imbalance), epigenetic regulation (histone modifications, non-coding RNAs), and regulated cell death (apoptosis, pyroptosis, ferroptosis) intensify calcification by releasing mineralization initiators and remodeling the ECM. This review emphasizes the complex interplay between metabolism-related calcification and proposes prospective treatment options, such as targeting metabolic checkpoints (e.g., PDK4, PPARγ), preventing phenotypic flipping, or influencing epigenetic reprogramming. These findings provide a theoretical foundation for the development of targeted therapies in the treatment of vascular calcification.