The dual role of extracellular vesicles in vascular calcification: from molecular mechanisms to clinical translation.

Vascular calcification (VC) is an active and regulated pathological process, which plays a central role in cardiovascular disease. Extracellular vesicles (EVs) are now recognized as crucial players in this pathology. EVs are nanoscale membrane vesicles secreted by cells. According to their biogenesis, they are mainly divided into exosomes, microvesicles and apoptotic bodies. They are rich in proteins, nucleic acids, lipids and other biologically active molecules. EVs play a dual role in VC. Regarding the pro-calcific role, EVs released by vascular smooth muscle cells (VSMCs), endothelial cells (ECs), and macrophages drive the phenotypic transformation of VSMCs by serving as nucleation cores for hydroxyapatite crystal deposition and by delivering pro-inflammatory and osteogenic signaling molecules. In addition to local effects, EVs also mediate long-distance intercellular communication. Together, these actions establish and amplify a pro-calcific microenvironment. In the aspect of anti-calcification, protective EVs can antagonize the osteogenic signaling pathway and maintain vascular homeostasis by delivering inhibitory microRNA (miRNA) (such as miR-126-5p, miR-133) and proteins (such as matrix Gla protein). The progress of VC depends on the balance between pro-calcific and anti-calcific EVs. Given their central position in pathology, EVs have become a highly promising source of new biomarkers, therapeutic intervention targets and drug delivery carriers. This review systematically summarizes the basic biological characteristics of EVs and the specific mechanisms underlying their dual regulatory roles in VC. It also discusses the challenges and future prospects for their clinical translation, thereby highlighting current knowledge gaps and outlining the exploratory nature of diagnostic and therapeutic strategies against VC.