Modulation of predicted key driver genes of an atherosclerosis-associated gene regulatory network in human endothelial cells

Carotid stenosis is a major cause of ischemic strokes both in males and females, but the clinical manifestation and carotid plaque histology differ. Single-cell RNA-Seq of endarterectomy samples from women and men revealed marked differences at the cell subtype level depending on sex. To provide clinical and pathophysiological context, cell subtypes displaying sex differences were integrated with 135 tissue-specific gene-regulatory networks (GRNs) of the STARNET study, leading to the identification of several atherosclerotic arterial wall sex-differential and cell-type-specific GRNs. PLVAP and FAM110D, two predicted key drivers of the male-dominant, endothelial cell-associated network GRN195 were overexpressed in human arterial endothelial cells (HAECs) to modulate the GRN and study its effect on cellular functions, including cell adhesion and proliferation.