Atherosclerosis, which underlies life-threatening cardiovascular disorders such as
myocardial infarction and stroke1, is initiated by passage of
low-density lipoprotein (
LDL) cholesterol into the artery wall and its engulfment by macrophages, which leads to foam cell formation and lesion development2,3. It is unclear how circulating
LDL enters the artery wall to instigate
atherosclerosis. Here we show in mice that
scavenger receptor class B type 1 (SR-B1) in endothelial cells mediates the delivery of
LDL 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 transcytosis of
LDL across endothelial monolayers requires its direct binding to SR-B1 and an eight-
amino-acid cytoplasmic domain of the receptor that recruits the
guanine nucleotide exchange factor dedicator of cytokinesis 4 (DOCK4)4. DOCK4 promotes internalization of SR-B1 and transport of
LDL by coupling the binding of
LDL to SR-B1 with activation of RAC1. The expression of SR-B1 and DOCK4 is increased in
atherosclerosis-prone regions of the mouse aorta before lesion formation, and in human atherosclerotic arteries when compared with normal arteries. These findings challenge the long-held concept that
atherogenesis involves passive movement of
LDL across a compromised endothelial barrier. Interventions that inhibit the endothelial delivery of
LDL into artery walls may represent a new therapeutic category in the battle against
cardiovascular disease.