Investigating Models of Coronary Artery Disease with Vascular Cell Transcriptomes

Abstract

Coronary artery disease is complex, arising from many genetic and environmental factors. Thedisease aetiology involves pathophysiology of multiple cell-types, which can be assayed using transcriptomic technologies. In this work, I present an investigation of vascular cell-type transcriptomes in both in vivo and in vitro models of atherosclerosis. Using a meta-analysis of singlecell RNA-seq datasets gathered from murine models of atherosclerosis, I determine that smooth muscle cell phenotypic plasticity shows a greater degree of transcriptional variability in vivo than in a previously developed cholesterol treatment assay in vitro. Furthermore, differentially expressed transcripts between smooth muscle lineage positive and smooth muscle lineage negative macrophages are identified. Human aortic endothelial cell co-expression clusters are identified in untreated and pro-inflammatory conditions and tested for association with common genetic variation, either as individual variants or as a polygenic risk score for coronary artery disease. I find little evidence that transcriptional modules are driven by common genetic variation in endothelial cells. In conclusion, transcriptomic assays and systems genetics allow for the investigation of complex disease processes, and further research is required to uncover the mechanisms governing smooth muscle phenotypic plasticity and endothelial transcriptional responses to common genetic variation.