Defining the role of vascular cell senescence in atherosclerosis: from plaque progression and instability to thrombotic risk
Description: Atherosclerosis is still the leading cause of death worldwide, and for a long time, was viewed primary as a lipid and leucocyte-driven process. Owing to lineage tracing and single cell technologies we know now that vascular smooth muscle cells (VSMCs) are far more abundant and plastic in the atherosclerotic plaque than originally thought. VSMCs also undergo cellular senescence during plaque progression which promotes plaque destabilisation through inflammation but whether there is a connection with VSMC phenotypic switching remains unclear. Moreover, whether SMC senescence can spread to the surrounding perivascular adipose tissue (PVAT), thereby amplifying vascular dysfunction and atherosclerosis has never been investigated. Also little is known about the role of cell senescence in atherothrombosis. Hence, the main objective is to identify the key mechanisms by which vascular cell senescence promotes atherosclerosis at the level of 1) the vasculature, 2) the perivascular tissue, and 3) the blood. The first aim is to study the role of RGS5 (Regulator of G-protein Signaling 5) in regulating VSMC senescence and plasticity, using 3D spheroids cultures, VSMC lineage tracing, senolytic drugs and a new model of atherosclerosis (i.e. viral overexpression of mPCSK9) that I recently established in my lab. The second aim is to study the bidirectional crosstalk between the (senescent) vascular wall and perivascular adipose tissue (PVAT) using multi-omics approaches. Thirdly, I will study the role of vascular cell senescence in atherothrombosis, and the therapeutic potential of senolytics and LOX-1 (lectin-like oxLDL receptor) inhibitors herein. Both LOX-1 inhibitors and certain senolytics may impose an increased risk of bleeding which could hamper its use in patients. Overall, the central aim is to find new molecular targets for anti-senescence therapies, with the ultimate goal of reducing the atherosclerosis burden and thrombotic risk in patients.
Funder: Vlaamse regering
Funding type: fellowship
Funder scheme: BOF - ZAP BOF mandates
Start date: 2025-09-01
End date: 2035-08-31
Investigator: Mandy Grootaert
Institution: KULeuven
Funded outputs count: 0
Funder award ID: vlaamse-74ab6b62-3890-4e53-8c2c-a3013451fe12
OpenAlex ID: G1720136329