Identifying novel targets to treat and prevent arterial disease

Progression of arterial disease is critically determined by the response of smooth muscle cells (SMCs) within the medial layer. In their fully differentiated, contractile state, SMCs confer stability and regulate vascular tone. However, disease induces a ‘contractile-synthetic’ phenotypic switch which impairs function, leads to vascular stiffness and exacerbates inflammation, to promote atherosclerosis and susceptibility to abdominal aortic aneurysm (AAA) (1). In animal studies, we have identified candidate pathways, based on knowledge of embryonic SMC differentiation, with the potential to protect against AAA1 and atherosclerosis (2) by preserving contractile SMC phenotype. However, the low success rate in translation from animal studies to the clinic highlights the need to determine whether similar mechanisms serve to protect the human vasculature, and how they may be targeted to alleviate disease.

The aim of the project is to establish human-relevant SMC models in which to study phenotypic switching and disease: i) a monoculture of human coronary artery SMCs; the simple monoculture model will permit evaluation of factors that directly impact SMC modulation, without confounding influences of other cell types.  ii) a more physiologically relevant model of hcSMCs co-cultured with coronary arterial endothelial cells. EC-SMC interaction crucially maintains vascular tone and functionality and dysregulation of this crosstalk underpins pathological remodelling e.g. in intimal hyperplasia. These models will then be used for high genetic and pharmacological screening to reveal disease-modifying targets. The most promising will be explored in murine disease models.
 

1). Munshaw et al. (2021) J Clin Invest 131.(10):e127884.

2). Munshaw, Redpath, Pike & Smart. bioRxiv, 2021.2011.2030.470548 (2021).