Increased oxidative stress and nicotine were reported to promote endothelial dysfunction.[16] In a setting of cigarette smoking, free radicals may arise either from the gas or the tar phase of cigarette smoke; initiate circulating or in situ-activated macrophages and neutrophils; and plays a role as endogenous sources for reactive oxygen species, such as uncoupled endothelial nitric oxide synthase, xanthine oxidase, and the mitochondrial electron transport chain.[2] The in vitro studies showed that nicotine decreased nitric oxide production and availability. This evidence concerns the gene NOS3 and endothelial dysfunction.