Genetic or therapeutic neutralization of ALK1 reduces LDL transcytosis and atherosclerosis in mice

Low-density lipoprotein (LDL) accumulation in the arterial wall contributes to atherosclerosis initiation and progression1. Activin A receptor-like type 1 (ACVRL1, called activin-like kinase receptor (ALK1)) is a recently identified receptor that mediates LDL entry and transcytosis in endothelial cells (ECs)2,3. However, the role of this pathway in vivo is not yet known. In the present study, we show that genetic deletion of ALK1 in arterial ECs of mice substantially limits LDL accumulation, macrophage infiltration and atherosclerosis without affecting cholesterol or triglyceride levels. Moreover, a selective monoclonal antibody binding ALK1 efficiently blocked LDL transcytosis, but not bone morphogenetic protein-9 (BMP9) signaling, dramatically reducing plaque formation in LDL receptor knockout mice fed a high-fat diet. Thus, our results demonstrate that blocking LDL transcytosis into the endothelium may be a promising therapeutic strategy that targets the initiating event of atherosclerotic cardiovascular disease. The bone morphogenetic protein (BMP) 9/10 receptor, ALK1, was recently shown to mediate LDL entry and transcytosis in endothelial cells. Here, Lee et al. show that genetic ablation of arterial endothelial ALK1 in mice limits atherosclerosis without affecting cholesterol or triglyceride levels and that a monoclonal antibody binding ALK1 efficiently blocks LDL transcytosis, but not BMP9 signaling, leading to a reduction in plaque burden.