Environmental and Genetic Regulation of Vascular Smooth Muscle Cell Gene Expression in Coronary Artery Disease

Coronary artery disease (CAD) remains a leading cause of mortality worldwide and is driven by complex interactions between genetic and environmental factors. Vascular smooth muscle cells (VSMCs) play a key role in the progression of atherosclerosis, the underlying driver of CAD. VSMCs are highly plastic cells that transition from a contractile, quiescent state to a synthetic, proliferative state capable of contributing to both plaque stability and vulnerability. This dissertation investigates the environmental and genetic regulation of VSMC gene expression in atherosclerosis through an integrative systems genetics framework. First, network preservation analysis of RNA-sequencing data between quiescent and proliferative VSMCs revealed condition-specific gene regulatory networks (GRNs) associated with metabolic pathways, including nitrogen and glycolysis-related processes, highlighting metabolism as a potential driver of phenotypic switching. Second, sex-stratified GRNs identified MYH9 as a female-biased key regulator of fibrous-associated processes. Single-cell RNA-sequencing and proteomics from atherosclerotic lesions supported the sex-specific regulation of MYH9 and fibrous plaque association. Third, fine-mapping of colocalized CAD-associated loci with VSMC splicing quantitative trait loci (sQTL) identified novel splicing-mediated mechanisms of disease risk. Long-read sequencing and isoform-specific analysis demonstrated that alternative splicing at PARP12 alters NF-kB signaling, implicating transcript diversity in inflammatory regulation. Together these findings reveal that VSMC gene expression is finely tuned by cellular context, sex, and genetic variation. This work emphasizes the utility of integrating GRNs, QTLs, and multi-modal omics datasets to dissect CAD pathophysiology and identify mechanistic links between the underlying regulators of vascular function. The insights presented here lay a foundation for future precision therapies targeting VSMC-driven pathways in CAD.