Shear stress modulates vascular structure and function through cytoskeletal remodeling and activation of signaling cascades. Elevated vascular endothelial growth factor (VEGF) concentrations are seen in atherosclerotic disease and after active increase of perfusion. Levels of soluble vascular cell adhesion molecule (sVCAM-1) are increased in atherosclerotic disease without strict correlation to disease progression. In vitro, increased shear stress induces a biphasic response of sVCAM-1. No data are available on in vivo downregulation of VEGF or sVCAM-1 in humans. In 24 healthy individuals, vascular function of lower extremities was assessed by plethysmography measuring flow-mediated dilation and through intra-arterial infusion of acetylcholine and nitroglycerine. Ten healthy individuals were challenged with cycle exercise testing. Cytokines were measured from citrate plasma from cubital and femoral vein blood. Plasma concentrations of VEGF and sVCAM-1 correlated with endothelium-dependent dilation. Two hours after acetylcholine-induced shear stress, plasma concentrations of sVCAM-1 levels were reduced by 31% (p <.001) locally and 18% (p <.05) systemically. Nitroglycerine produced similar local and systemic suppression (36% and 34%; p <.0001). Immediately after exercise, concentrations of sVCAM-1 increased with a significant decrease one hour later (-9%; p <.01). VEGF increased after infusion of nitroglycerine (+35%; p <.05) and dropped after 1 h of 30-min exercising (-31%, p <.05). This is the first study to show changes of sVCAM-1 in vivo. Changes of VEGF and sVCAM-1 in humans seem time, magnitude, and substance specific. Short acting suppression of VEGF and SVCAM-1 under physiological conditions may explain exercise-induced vascular protection and the lack of correlation of these cytokines with activity of atherosclerotic disease.