Calcific aortic valve disease (CAVD) is a prevalent and progressive disorder marked by fibrocalcific remodeling of the aortic valve, for which no effective pharmacological therapies currently exist. While CAVD is recognized as an active, cell-driven process, the intercellular communication networks that govern pathological valve remodeling are not fully understood. Extracellular vesicles (EVs) have emerged as key mediators of such communication in cardiovascular disease, transferring bioactive molecules like microRNAs (miRNAs) between cells to influence disease progression. This review synthesizes the current understanding of EV-mediated miRNA signaling in cardiovascular calcification, with a specific focus on its emerging role in CAVD. We discuss the established functions of EV-miRNAs in vascular disease and calcification and then examine recent paradigm-shifting evidence regarding miR-145-5p in the valvular context. Contrary to its well-established protective role in vascular smooth muscle cell homeostasis, recent work demonstrates that endothelial-derived EVs enriched in miR-145-5p are taken up by valvular interstitial cells (VICs), where they promote osteogenic reprogramming under calcifying conditions. This finding challenges the generalized view of miR-145-5p as a universally anti-calcific agent and highlights a critical dependence on cellular context and mode of intercellular transfer. By positioning EV-associated miR-145-5p as an active signaling molecule in valve calcification, this review underscores the complexity of miRNA function in different cardiovascular compartments and emphasizes the need to consider the specific cellular origin and delivery mechanisms when investigating the pathophysiology of CAVD.

Calcific aortic valve disease, Cardiovascular therapeutics, Extracellular vesicles, microRNAs, MiR-145-5p, RNA therapeutics, Valve calcification