Shear Stress Mediates Endothelial Adaptations to Exercise Training in Humans

Although episodic changes in shear stress have been proposed as the mechanism responsible for the effects of exercise training on the vasculature, this hypothesis has not been directly addressed in humans. We examined brachial artery flow-mediated dilation, an index of NO-mediated endothelial function, in healthy men in response to an acute bout of handgrip exercise and across an 8-week period of bilateral handgrip training. Shear stress responses were attenuated in one arm by cuff inflation to 60 mm Hg. Similar increases were observed in grip strength and forearm volume and girth in both limbs. Acute bouts of handgrip exercise increased shear rate (P0.005) and flow-mediated dilation percentage (P0.05) in the uncuffed limb, whereas no changes were evident in the cuffed arm. Handgrip training increased flow-mediated dilation percentage in the noncuffed limb at weeks 2, 4, and 6 (P0.001), whereas no changes were observed in the cuffed arm. Brachial artery peak reactive hyperemia, an index of resistance artery remodeling, progressively increased with training in the noncuffed limb (P0.001 and 0.004); no changes were evident in the cuffed arm. Neither acute nor chronic shear manipulation during exercise influenced endothelium-independent glyceryl trinitrate responses. These results demonstrate that exercise-induced changes in shear provide the principal physiological stimulus to adaptation in flow-mediated endothelial function and vascular remodeling in response to exercise training in healthy humans. (Hypertension. 2010;55:00-00.) The mechanisms responsible for the benefits of exercise training in terms of endothelial function may be related to either direct hemodynamic effects, or secondary effects, mediated through risk factor modification. We have previ- ously demonstrated that improvements in vascular function with exercise training can occur without change in traditional risk factor profiles,11 whereas exercise is known to be associated with acute changes in endothelial shear stress.12,13 It has therefore been proposed that episodic increases in shear stress may be the mechanism responsible for the beneficial impact of exercise training on vascular function.14,15 Indeed, increases in intraluminal shear stress improve NO-mediated endothelium-dependent dilation in animals. 16,17 However, to our knowledge, this has not been directly addressed experi- mentally in humans. In the present study, we took advantage of a within-subject design, involving simultaneous 8-week handgrip training of identical exercise intensity and duration of both forearms. During these supervised exercise bouts (30-minute, 4 times a week), shear stress was manipulated in one arm using cuff inflation, such that it remained near resting levels. We examined indices of endothelium-dependent artery function and remodeling at 2-week intervals over the 8-week training period. We hypothesized that changes in endothelial function and artery remodeling would be diminished in the limb exposed to lower shear stress stimulation during training.