UC San Diego

Endothelial cells covering the inner surface of blood vessels are constantly exposed to shear stresses. Such hemodynamic shear stress influences vascular functions, and any endothelial dysfunction can lead to the progression of cardiovascular diseases, such as atherosclerosis. Atherosclerotic plaque formation in the endothelium is shown to be site-specific: disturbed flow regions at lesser curvature of the aortic arch and branched points are sites that are more susceptible to plaque formation, whereas steady flow regions at greater curvature and straight parts are more atheroprotective and maintain vascular homeostasis. Previous researches have extensively studied the various biochemical pathways implicated in atherosclerosis. Recently, increased attention has been granted to epigenetics to study the chromatin-based mechanisms in the nucleus involved in the regulation of gene expression in a DNA-independent manner. Studies have shown that histone modifications, such as methylation, are involved in different shear stress patterns. This thesis aims to compare the effects exerted by pulsatile shear (PS) and oscillatory shear (OS) on histone modifications, specifically H3K9 di- and tri- methylation (H3K9me2, and H3K9me3), in human umbilical vein endothelial cells (HUVECs) for 24 hours through chromatin immunoprecipitation followed by high throughput sequencing (ChIP-seq). Bioinformatics analysis of the flow-regulated H3K9me2/me3 enrichment genes using gene ontology (GO) analysis, reveals pathways of mechnotransduction, inflammation, proliferation, migration, and apoptosis, are involved in the atheroprotective effects of PS. Based on the identification of the downstream effects of PS, such findings could be helpful in elucidating the various epigenetic elements involved in the development of atherosclerosis.