Mechanisms of vascular smooth muscle cell ageing and calcification – towards novel therapeutic interventions.

Ageing is the strongest risk factor for the development of vascular calcification, a detrimental, prevalent pathology for which there is no treatment. Calcification is caused by vascular smooth muscle cell (VSMC) dysfunction. We have shown that as VSMCs age they accumulate prelamin A, a toxic nuclear protein that drives epigenetic modifications, DNA damage, premature senescence/inflammation, extracellular matrix (ECM) remodeling and ultimately calcification. We have characterized two animal models of accelerated vascular ageing induced by prelamin A accumulation; one exhibiting aortic dilatation and the second medial vascular calcification and have used multi-omics to identify temporal pathways to pathology. We have also described a unique epigenetic signature that precedes the onset of the inflammatory and osteogenic pathways driving calcification and identified the DNA damage response (DDR) as a key signaling pathway regulating the master osteogenic transcription factor Runx2. Using these mouse models and tissue samples from children with Chronic Kidney Disease (CKD) we will (1) dissect at the single cell level VSMC phenotypic change comparing cell populations in calcified arteries in animal models with human disease and (2) determine the molecular mechanisms whereby epigenetics and the DDR regulate inflammation, VSMC osteogenic differentiation and calcification integrating the screening and testing of novel therapeutics.