Harnessing the potential of smooth muscle cells for therapy in atherosclerotic vascular disease

Smooth muscle cells (SMCs) are the main structural vessel component.

In cardiovascular diseases (CVD) underlined by atherosclerosis, the balance of excessive vs insufficient SMC activation, along with their plasticity, determines the vessel healing response.

SMCs functionally trans-differentiate elicited by pathological stimuli into multiple subphenotypes, which critically affects plaque vulnerability. Yet, there are currently no CVD therapies specifically targeting SMCs.

Our hypothesis is that exploration of pathways controlling SMC subphenotypes can lead to novel strategies to support their healing capacity.

We seek to 1) discover druggable targets that regulate SMC plasticity and 2) evaluate the implementation of SMC therapies, beyond the best available treatments.

We will develop in silico exploration of a large atherosclerosis biobank to identify SMC targets by: a) multi-omics data integration, b) deconvolved by single-cell RNA signatures of SMC subphenotypes, c) stratified by clinical parameters and d) enriched with genetic CVD association data.

SMC targets will be investigated mechanistically in vitro and druggability evaluated via proof-of-concept in vivo models.

We will test complementation of current therapies with SMC-targeted plaque stabilisation, to alleviate total disease burden.With this translational approach, the project will push the knowledge frontier about SMC subphenotypes in human lesions and pave the way for a paradigm shift in treatment of complex CVD.