Abstract 268: Single Cell Gene Expression Of Brachial Artery In Response To Increased Shear Stress

Abstract

Blood flow dynamics modulate vascular development, homeostasis, and contribute to vascular pathobiology. However, it is unknown how shear stress influences cellular transcriptomics of the arterial wall. Two-stage hemodialysis access surgeries provide an opportunity to compare native vessel to vessel after exposure to significantly altered hemodynamics. Single-cell sequencing was performed on brachial artery samples obtained from 3 patients at the time of 1 st and 2 nd stage surgery. Arterial cellular composition and temporal changes in gene expression were quantified after sequencing and functional analyses were performed on differentially expressed genes. Compositional changes and gene expression dynamics were highest in the smooth muscle cell (SMC) populations followed by fibroblasts. SMCs were clustered into contractile (classical) and “modified” populations, with the latter having lower expression of contractile markers. Downregulation of transcription factor ARNTL was the most significant controller in contractile SMCs and fibroblasts, and second behind HIF1α in modified SMCs. Macrophages had a significant increase in composition, but few dynamic genes suggest a return to quiescence. Endothelial cells showed minimal changes with dynamic genes responding to mechanical stimulus. Ingenuity pathway analysis revealed activation of EIF2 signaling in both SMC and fibroblast clusters, promoting translation. The top divergent pathway among SMC clusters is PI3/AKT signaling, with increased vascular remodeling, proliferation and cell death in the contractile group. Cellular processes are overall downregulated in modified SMCs, which represent the majority of SMCs after vascular adaption. This study is the first single-cell characterization of normal human artery and its cellular response to increased hemodynamic forces, specifically detailing cellular compositional changes and their associated dynamic genes.