Abstract
<jats:p>Atherosclerosis is initiated by circulating low-density lipoprotein (LDL) cholesterol transfer into the artery wall, which is mediated by scavenger receptor class B, type I (SR-BI) in endothelial cells(1). Employing single-cell RNA sequencing in human coronary artery disease (CAD) samples, here we show that endothelial SR-BI expression is increased in atheroma, and in endothelial cells with a transcript signature indicative of responding to disturbed blood flow. In vivo in mice hypercholesterolemia and disturbed blood flow independently upregulate endothelial SR-BI; the flow-related upregulation initiates endothelial cell LDL uptake and atherogenesis. Guided by transcription factor networks, it is revealed that HIF-1α binding to human Scarb1 Intron 1 governs endothelial SR-BI transcription, and in mice HIF-1α drives hypercholesterolemia-related SR-BI upregulation and artery LDL uptake. Thus, the two major instigators of atherosclerotic lesion formation, hypercholesterolemia and disturbed blood flow, both upregulate endothelial SR-BI to drive the LDL transport that underlies the disorder. Targeting the processes regulating endothelial SR-BI potentially represents a new therapeutic strategy against CAD.</jats:p>