Using a novel human 3D spheroid model to study mechanisms and therapeutics for vascular calcification

Start date: October 2025

Vascular calcification (VC) is a serious and widespread clinical problem manifesting in atherosclerosis, chronic kidney disease (CKD), diabetes and ageing. It is an independent risk factor for cardiovascular mortality in all disease contexts. Currently, there are no treatments to prevent or regress vascular calcification. Therefore, there is a serious unmet clinical need to understand the molecular mechanisms driving the calcification process, and to identify novel treatment strategies.

VC is a cell-mediated process, driven by vascular smooth muscle cells (VSMCs). Signalling pathways activated in response to stressors cause VSMCs to undergo a phenotypic change and conversion to osteo/chondrogenic cells capable of orchestrating the calcification process. Concomitantly, loss of calcification inhibitors primes the vessel for mineralization while necrotic and apoptotic cell death, as well as release of extracellular vesicles (EVs) act as nucleation sites for hydroxyapaptite (HA) formation.

Current preclinical research into vascular calcification relies heavily on animal models or on the use of 2D in vitro models of VSMCs grown on plastic. All these models require that calcification is induced via the addition of elevated levels of calcium or phosphate which does not mimic key in vivo pathways to calcification. To address this deficit we have developed two novel in vitro models of vascular calcification that can induce VSMC osteochondrogenic differentiation and mineralisation without the need for additional stimuli. We propose to use these models to determine novel mechanisms of calcification and in high throughput screening platforms for drugs that inhibit the process.

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