Vascular Calcification: Mechanisms, Models, and Therapies

ABSTRACT Vascular calcification represents an active multifactorial process that mirrors several key features of skeletal bone mineralization. Clinically, it is characterized by diminished arterial compliance and increased arterial wall stiffness, both of which serve as independent predictors of significant adverse cardiovascular events. The primary cellular mechanism involves the phenotypic transformation of contractile vascular smooth muscle cells (VSMCs) into osteo/chondrogenic‐like cells, which produce an extracellular matrix conducive to hydroxyapatite deposition. This transdifferentiation is regulated by intricate cellular signaling networks, including the BMP‐Smad signaling pathway, both canonical and non‐canonical Wnt/β‐catenin pathways, Stat3 activated by inflammatory cytokines, the Notch signaling pathway, and ROS‐activated MAPK (ERK/p38) and NF‐κB pathways. In contrast, the SIRT family proteins (such as nuclear SIRT1/SIRT6), extracellular pyrophosphate (PPi), and matrix Gla protein (MGP) exert inhibitory effects on vascular calcification. Anatomically, calcification can be localized to the intimal layer, often superimposed on advanced atherosclerotic plaques in large conduit arteries, or to the medial layer, a pattern characteristic of small‐ to medium‐sized muscular arteries, known as Mönckeberg's sclerosis. Despite extensive research efforts, the molecular mechanisms governing mineral deposition in vascular tissues remain inadequately understood, and no pharmacological intervention has yet been demonstrated to be both safe and effective in preventing or reversing established calcification. In this review, we examine current insights into the pathobiology of vascular calcification, critically evaluate available in vitro models (including human aortic smooth muscle cells, endothelial cells, and valvular interstitial cell calcification models) and in vivo models (such as pharmacologically induced and genetically modified or surgical models) and highlight emerging therapeutic targets and agents that are currently under preclinical or early clinical investigation.