Accumulation of LDL in the artery wall is critical to atherosclerosis initiation and progression. However, the precise mechanisms controlling LDL entry into the artery wall are not fully understood. A study published in Nature shows that scavenger receptor class B member 1 (SRB1) in endothelial cells mediates active transcellular transport of circulating LDL into the artery wall and thereby fosters the accumulation of LDL in macrophages, which become foam cells and promote the development of atherosclerosis. “These findings challenge the long-held concept that the LDL entry into the artery wall that drives atherosclerosis occurs passively at sites of injury or disruption of the endothelial barrier,” says lead investigator Philip Shaul.

To gain insight into the role of endothelial SRB1 in atherosclerosis, Shaul and colleagues deleted the SRB1-encoding gene Scarb1 specifically in endothelial cells in three mouse models of atherosclerosis, and using confocal fluorescence microscopy, they visualized LDL entry into arteries in vivo. The research team had shown previously that SRB1, which is a receptor for both HDL and LDL, mediates many potential protective, anti-atherosclerotic actions of HDL in endothelial cells. “Therefore, at the outset of the studies, we expected that the loss of SRB1 from endothelial cells in mice with hypercholesterolaemia would result in worse atherosclerosis,” explains Shaul. “To our initial surprise, deletion of Scarb1 from endothelial cells yielded considerably less atherosclerosis than in control mice,” he adds. By contrast, mice with specific deletion of Scarb1 in hepatocytes had increased atherosclerosis, indicating that SRB1 in endothelial cells and hepatocytes has contrasting effects on cardiovascular health.

SRB1 deficiency in endothelial cells had no effect on circulating lipids or vascular inflammation in mice, but resulted in lower LDL delivery to the artery wall than in control mice. In addition, the investigators found that LDL particles co-localized with SRB1 in intracellular vesicles within endothelial cells in vivo. Mechanistically, the researchers determined that trafficking of LDL into and across endothelial monolayers requires direct binding of LDL to SRB1 and SRB1 recruitment of dedicator of cytokinesis protein 4 (DOCK4). DOCK4 in turn promotes SRB1 internalization and LDL transport by activating the RHO GTPase RAC1. SRB1 and DOCK4 levels were higher in atherosclerosis-prone regions than in atherosclerosis-resistant regions of the mouse aorta prior to lesion formation, and in human atherosclerotic arteries compared with normal arteries.

Shaul comments that they are now exploring the possibility of using gene therapy or pharmacological intervention to reduce the function of SRB1 or DOCK4 in endothelial cells as a strategy to prevent atherosclerosis.