Vascular calcification: pathogenic mechanisms, signaling crosstalk and translational therapeutics

Vascular calcification (VC) is a multifactorial pathological process characterized by ectopic deposition of hydroxyapatite in the arterial wall, which is closely associated with increased cardiovascular morbidity and mortality. This review provides a comprehensive synthesis of current insights into the pathogenesis of VC, emphasizing its nature as a dynamically regulated process driven by intricate crosstalk among diverse molecular mechanisms, signaling cascades, and pathological pathways. Under specific pathological stimuli, this intricate regulatory network disrupts the homeostatic balance between pro-calcific and anti-calcific mechanisms. Key drivers of VC include the phenotypic transformation of vascular smooth muscle cells (VSMCs), endothelial-to-mesenchymal transition (EndMT), inflammation, oxidative stress, endoplasmic reticulum stress, mitochondrial dysfunction, and various forms of programmed cell death. The transcription factor RUNX2 serves as a central regulator, integrating signals from pathways such as WNT/β-catenin, BMP/Smad, PI3K/AKT, MAPK, AMPK, NF-κB, Notch, and Rho/ROCK. Furthermore, emerging evidence highlights the critical regulatory roles of epigenetic mechanisms, including posttranslational modifications (PTMs) and noncoding RNAs (lncRNAs, miRNAs, circRNAs). Given the complexity of VC, we critically evaluate the efficacy and safety of various pharmacological interventions from clinical trials, including bisphosphonates (BPs), calcimimetics, phosphate binders, dipeptidyl peptidase-4 inhibitor (DPP4i), SNF472, sodium-glucose cotransporter 2 inhibitors (SGLT2i), statins, proprotein convertase subtilisin/kexin type 9 inhibitors (PCSK9i), sodium thiosulfate, and vitamins K and D, while also discussing potential endogenous molecules and natural compounds. A deep understanding of these interconnected molecular networks is essential for developing precision therapies to mitigate VC and VC-related cardiovascular complications.