Leducq-funded network: calcification-omics, molecular elucidation, and therapeutics (COMET)

Vascular calcification is a highly prevalent and clinically significant pathology affecting both women and men across all ages. It manifests in the intima or media of small and large arteries with genetic, age-associated, and metabolic diseases. Vascular calcification is among the strongest independent predictors of cardiovascular events, including myocardial infarction (MI), stroke, and peripheral arterial disease,1,2 and is often fatal in conditions such as calciphylaxis and rare genetic syndromes such as generalized arterial calcification of infancy.3,4 The global burden of vascular calcification is rising due to ageing populations and the increasing prevalence of diabetes and chronic kidney disease (CKD). However, despite its clinical relevance, no targeted therapies currently exist. Vascular calcification is regulated by both biological and physicochemical processes that drive calcium and phosphate mineral deposition within the extracellular matrix (ECM) of the vessel wall. Calcification can occur throughout the arterial tree, with distinct tissue-specific patterns and anatomical locations of the mineral that influence clinical outcomes. For instance, medial calcification causes arterial stiffening, contributing to pressure overload and organ damage, particularly to the heart and brain.5 In atherosclerotic intimal calcification, small, spotty calcium deposits correlate most strongly with plaque instability and poor prognosis, although both small and large deposits may contribute to plaque progression, erosion, and rupture.6,7 Once thought to be unmodifiable, vascular calcification is now recognized as a potentially reversible process. Mounting evidence suggests that halting or even reversing calcification could meaningfully improve cardiovascular health. Hence, the passion that drives the COMET investigators results from a simple central hypothesis: targeting vascular calcification may significantly reduce cardiovascular morbidity and mortality. Focused research over the last 20 years using in vitro models and animal and human studies has identified vascular smooth muscle cells (VSMCs) as central orchestrators of calcification. Endothelial cells (ECs), inflammatory cells, and adventitial fibroblasts also play important roles. Key mechanisms include the loss of calcification inhibitors (produced by VSMCs or circulating in the serum), osteochondrogenic differentiation of vascular cells, and the nucleation of mineral deposits on extracellular vesicles or the ECM. However, critical knowledge gaps remain, particularly regarding the identity of cell populations and key molecular regulators that drive or prevent calcification across different disease contexts. The heterogeneity of VSMCs and the tissue-specific nature of calcification represent major obstacles. Most existing studies focus narrowly on known transcription factors and signalling pathways, often reinforcing prevailing dogma and overlooking novel regulators. Emerging single-cell and spatial ‘omics’ technologies now offer unbiased, high-resolution insights into VSMC phenotypic plasticity both temporally and spatially. Integrating these multimodal datasets with large-scale human genetics will be essential to uncovering actionable targets and novel biological mechanisms. Equally underexplored is the composition of the mineral and how it is formed and modulated by chemical processes occurring in the ECM microenvironment. Ageing, a major risk factor for vascular calcification, alters ECM structure and function via enzymatic and non-enzymatic modifications, disrupting ECM-cell signalling, cell differentiation, and vascular remodelling.8 However, the causal relationships between specific ECM modifications and underlying cellular changes and calcification remain poorly defined. Recent multi-ancestry genome-wide meta-analyses have uncovered novel loci associated with coronary artery calcification.9,10 Yet, there remains a gap in identifying causal biomarkers to improve patient risk stratification across ancestry and sex. Furthermore, there is an urgent need for novel imaging agents that selectively bind distinct ECM components or mineral phases, enabling earlier and more precise detection. Progress in understanding the genesis and progression of vascular calcification demands an interdisciplinary approach—one that links biological and chemical insights and bridges basic science with clinical translation. The COMET network embodies this vision, bringing together an expert team of cardiologists, nephrologists, biotechnologists, biologists, bioinformaticians, and chemists to develop novel targeted therapies for patients suffering from calcification-related diseases. Led by Drs Rajeev Malhotra (North American co-ordinator; Mass General Brigham, Boston, MA, USA), Catherine M. Shanahan (European co-ordinator; King’s College London, London, UK), Clint L. Miller (University of Virginia, Charlottesville, VA, USA), Yabing Chen (Oregon Health & Sciences University, Portland, OR, USA), Melinda J. Duer (University of Cambridge, Cambridge, UK), Maryam Kavousi (University Medical Center Rotterdam, Rotterdam, The Netherlands), and Rafael Kramann (RWTH Aachen University, Aachen, Germany), COMET is uniquely positioned to tackle this complex pathology. The network is focused on several key priorities, critical to the development of new therapeutics: (i) defining culprit VSMC and EC sub-populations in different disease contexts, (ii) discovering new molecular targets and regulatory pathways, and (iii) understanding how the ageing ECM modulates cell phenotype and nidus formation in different vascular niches. COMET leverages genetic and multi-omic datasets, advanced physicochemical imaging, and in vitro and in vivo models to uncover how molecular, cellular, and matrix-level factors interact to drive the mineralization process (Figure 1). These data will inform both candidate-based and AI-enabled therapeutic strategies, applicable to rare genetic disorders and common cardiovascular diseases in the general population. Overview of workflow in the COMET network to identify causal regulators and modifiers of vascular calcification. The figure was created using BioRender Supported by the Leducq Foundation, COMET is committed to pushing the envelope forward in our understanding of vascular calcification and associated highly morbid and age-accelerated human diseases, such as MI, stroke, CKD, diabetes, and calciphylaxis. We are also strongly committed to training the next generation of scientists. This collaborative network provides a powerful training platform for emerging investigators to develop interdisciplinary expertise and skills required to make meaningful and lasting contributions in the fight against vascular calcification. All authors declare no disclosure of interest for this contribution. The research described in this paper is made possible by a Fondation Leducq Network of Excellence grant (#24CVD02) given to all co-authors, the COMET consortium.