SR-B1 drives endothelial cell LDL transcytosis via DOCK4 to promote atherosclerosis

Abstract

SUMMARYAtherosclerosis, which underlies life-threatening cardiovascular disorders including myocardial infarction and stroke1, is initiated by low density lipoprotein cholesterol (LDL) passage into the artery wall and engulfment by macrophages, leading to foam cell formation and lesion development2, 2, 3, 3. How circulating LDL enters the artery wall to instigate atherosclerosis is unknown. Here we show in mice that scavenger receptor, class B type 1 (SR-B1) in endothelial cells mediates LDL delivery into arteries and its accumulation by artery wall macrophages, thereby promoting atherosclerosis. LDL particles are colocalized with SR-B1 in endothelial cell intracellular vesicles in vivo, and LDL transcytosis across endothelial monolayers requires its direct binding to SR-B1 and an 8 amino acid cytoplasmic domain of the receptor that recruits the guanine nucleotide exchange factor dedicator of cytokinesis 4 (DOCK4)4. DOCK4 promotes SR-B1 internalization and LDL transport by coupling LDL binding to SR-B1 with Rac1 activation. SR-B1 and DOCK4 expression are increased in atherosclerosis-prone regions of the mouse aorta prior to lesion formation, and in human atherosclerotic versus normal arteries. These findings challenge the long-held concept that atherogenesis involves passive LDL movement across a compromised endothelial barrier. Interventions inhibiting endothelial delivery of LDL into the artery wall may represent a new therapeutic category in the battle against cardiovascular disease.