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Background: Alcohol (ethanol) consumption has different influences on arterial disease, being protective or harmful depending on the amount and pattern of consumption. The mechanisms mediating these biphasic effects are unknown. Whereas endothelial cells play a critical role in maintaining arterial health, this study compared the effects of moderate and high alcohol concentrations on endothelial cell function. Methods: Human coronary artery endothelial cells (HCAEC) were treated with levels of ethanol associated with either low‐risk/moderate drinking (i.e., 25 mM) or high‐risk/heavy drinking (i.e., 50 mM) after which endothelial function was assessed. The effect of ethanol's primary metabolite acetaldehyde (10 and 25 μM) was also determined. Results: Moderate ethanol exposure (25 mM) improved HCAEC barrier integrity as determined by increased transendothelial electrical resistance (TEER), inhibited cell adhesion molecule (CAM) mRNA expression, decreased inflammatory cytokine (interferon‐γ and interleukin 6) production, inhibited monocyte chemotactic protein‐1 (MCP‐1) expression and monocyte adhesion, and increased homeostatic Notch signaling. In contrast, exposure to high‐level ethanol (50 mM) decreased TEER, increased CAM expression and inflammatory cytokine production, and stimulated MCP‐1 and monocyte adhesion, with no effect on Notch signaling. Reactive oxygen species (ROS) generation and endothelial nitric oxide synthase activity were increased by both alcohol treatments, and to a greater extent in the 50 mM ethanol group. Acetaldehyde‐elicited responses were generally the same as those of the high‐level ethanol group. Conclusions: Ethanol has biphasic effects on several endothelial functions such that a moderate level maintains the endothelium in a nonactivated state, whereas high‐level ethanol causes endothelial dysfunction, as does acetaldehyde. These data show the importance of dose when considering ethanol's effects on arterial endothelium, and could explain, in part, the J‐shaped relationship between alcohol concentration and atherosclerosis reported in some epidemiologic studies. [ABSTRACT FROM AUTHOR]