ApoB-containing lipoproteins regulate angiogenesis by modulating expression of VEGF receptor 1

High concentrations of some types of plasma lipoproteins, such as low-density lipoprotein, promote atherosclerosis and a wide range of vascular-related diseases. These pathogenic lipoproteins have in common the protein component apolipoprotein B. Through study of the effects of modulating lipoprotein levels in experiments involving zebrafish, mice and cultured human endothelial cells, Inbal Avraham-Davidi et al . uncover a potentially deleterious role of apolipoprotein B–containing lipoproteins as direct inhibitors of the angiogenic behavior of vascular endothelial cells. Despite the clear major contribution of hyperlipidemia to the prevalence of cardiovascular disease in the developed world, the direct effects of lipoproteins on endothelial cells have remained obscure and are under debate. Here we report a previously uncharacterized mechanism of vessel growth modulation by lipoprotein availability. Using a genetic screen for vascular defects in zebrafish, we initially identified a mutation, stalactite ( stl ), in the gene encoding microsomal triglyceride transfer protein ( mtp ), which is involved in the biosynthesis of apolipoprotein B (ApoB)-containing lipoproteins. By manipulating lipoprotein concentrations in zebrafish, we found that ApoB negatively regulates angiogenesis and that it is the ApoB protein particle, rather than lipid moieties within ApoB-containing lipoproteins, that is primarily responsible for this effect. Mechanistically, we identified downregulation of vascular endothelial growth factor receptor 1 (VEGFR1), which acts as a decoy receptor for VEGF, as a key mediator of the endothelial response to lipoproteins, and we observed VEGFR1 downregulation in hyperlipidemic mice. These findings may open new avenues for the treatment of lipoprotein-related vascular disorders.