OBJECTIVE: To study whether qualitative changes in high-density lipoprotein (HDL) phospholipids mediate part of the beneficial effects of alcohol on atherosclerosis, we investigated whether phosphatidylethanol (PEth) in HDL particles affects the secretion of vascular endothelial growth factor (VEGF) from endothelial cells. METHODS AND RESULTS: PEth increased the secretion of VEGF into the culture medium of EA.hy 926 endothelial cells. The mitogen-activated protein kinase (MAPK) phosphorylation increased by 3.3-fold and protein kinase C (PKC) by 2.2-fold by PEth-containing HDL. Moreover, we showed that intravenous injection of PEth incorporated into HDL particles increased plasma concentration of VEGF by 2.4-fold in rats in vivo. Similar effect was observed when the rats were injected with HDL particles isolated from alcohol drinkers. CONCLUSIONS: HDL particles containing PEth affect endothelial cells by MAPK and PKC signaling. This may mediate the effects of ethanol on the arterial wall by increasing VEGF secretion from endothelial vascular cells. That may explain, at least in part, the beneficial effect of moderate alcohol consumption on atherosclerosis.