Exploring Macrophage Contribution to Vascular Calcification in Atherosclerosis

Vascular calcification (VC) is a significant pathological feature of atherosclerosis, contributing to cardiovascular morbidity and mortality, particularly in populations with diabetes and chronic kidney disease (CKD). This review examines the pivotal role of macrophages in the development and progression of VC within atherosclerotic plaques. We explore the diverse phenotypes of macrophages, particularly the pro-inflammatory M1 and anti-inflammatory M2 types, and their distinct functions in modulating vascular smooth muscle cell (VSMC) behavior. M1 macrophages promote osteogenic signaling through the secretion of pro-inflammatory cytokines and growth factors, such as oncostatin M (OSM) and bone morphogenetic proteins (BMP), which facilitate VSMC transdifferentiation and calcification. Conversely, M2 macrophages exhibit protective properties that may mitigate excessive calcification. Furthermore, we discuss the intricate balance of these macrophage populations in atherosclerotic lesions and their influence on osteoclastic differentiation, which can either enhance or inhibit the resorption of calcified deposits. Recent findings on the involvement of microRNAs (miRNAs) in regulating macrophage activation and their impact on VC highlight potential therapeutic targets for mitigating this process. By elucidating the cellular and molecular mechanisms underpinning macrophage-mediated calcification, this review aims to provide insights into the dual roles of macrophages in atherosclerosis and their significance as potential therapeutic targets. Understanding these dynamics may lead to innovative strategies for preventing VC and improving cardiovascular health outcomes, particularly in patients with diabetes and CKD. © 2025 Elsevier B.V., All rights reserved.