REVIEW article
Front. Cardiovasc. Med.
Sec. Atherosclerosis and Vascular Medicine
Volume 12 - 2025 | doi: 10.3389/fcvm.2025.1664067
This article is part of the Research TopicCardiovascular calcification: disease mechanisms, clinical phenotypes and therapeutic strategiesView all 10 articles
Macrophages as key modulators of calcific aortic valve disease
Provisionally accepted- 1UR UPJV 7517, MP3CV, CURS, University of Picardie Jules Verne, Amiens, France
- 2Department of Biochemistry and Endocrine Biology, CHU AMIENS PICARDIE, Amiens, France
- 3Department of Pharmacology, CHU AMIENS PICARDIE, Amiens, France
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Calcific aortic valve disease (CAVD), defined by thickening, fibrosis, and mineralization of the aortic valve (AV) leaflets, is the most common valvular heart disease worldwide. This progressive remodeling gradually impairs valve opening, obstructing blood flow. Without intervention, the resulting aortic stenosis (AS) causes hemodynamic deterioration that ultimately leads to heart failure and death. To date, therapeutic options remain limited, making valve replacement the reference treatment. While valvular endothelial and interstitial cells have traditionally been considered the primary drivers of the osteogenic program underlying AV remodeling, recent evidence highlights a central role for macrophages, whose plasticity profoundly impacts the local microenvironment. In their inflammatory state, macrophages release cytokines, generate oxidative stress, and secrete Bone Morphogenetic Protein 2 (BMP2), which promotes the osteogenic transformation of valvular cells. The resulting calcium crystal deposition further amplifies macrophage-driven inflammation, creating a vicious cycle. Conversely, immunomodulatory macrophages can protect against CAVD by releasing pyrophosphate, a calcification inhibitor. However, these macrophages also secrete pro-fibrotic factors and may undergo myeloid-to-mesenchymal transition, processes that paradoxically contribute to AV fibrosis and mineralization. In addition, macrophages within the AV can differentiate into osteoclast-like cells, suggesting that a bone-like remodeling process occurs in the cardiovascular wall. This high phenotypic plasticity complicates our understanding of CAVD pathogenesis and highlights the need for deeper insight into macrophage functions to design effective preventive and therapeutic strategies. This review summarizes the mechanisms through which different macrophage subsets promote, prevent, or reverse AV remodeling, in both native and bioprosthetic contexts, and explores the therapeutic potential of targeting macrophages or their activity to slow AS progression.
Keywords: Aortic Valve, Calcific aortic valve disease, Macrophages, Inflammation, Novel therapies for bacterial infections
Received: 11 Jul 2025; Accepted: 05 Sep 2025.
Copyright: © 2025 ISSA, BLOT, CANDELLIER, BOUDOT, LOUVET, KAMEL, BENNIS and HENAUT. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
* Correspondence: Lucie HENAUT, UR UPJV 7517, MP3CV, CURS, University of Picardie Jules Verne, Amiens, France
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