Abstract-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 (PϽ0.005) and flow-mediated dilation percentage (PϽ0.05) 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 (PϽ0.001), 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 (PϽ0.001 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;55:312-318.)

Abstract-Shear stress is an important stimulus to arterial adaptation in response to exercise and training in humans. We recently observed significant reverse arterial flow and shear during exercise and different antegrade/retrograde patterns of shear and flow in response to different types of exercise. The purpose of this study was to simultaneously examine flow-mediated dilation, a largely NO-mediated vasodilator response, in both brachial arteries of healthy young men before and after 30-minute interventions consisting of bilateral forearm heating, recumbent leg cycling, and bilateral handgrip exercise. During each intervention, a cuff inflated to 60 mm Hg was placed on 1 arm to unilaterally manipulate the shear rate stimulus. Key Words: conduit artery Ⅲ flow-mediated dilation Ⅲ exercise training E xercise training is a well-established and potent physiological stimulus that reduces primary 1-3 and secondary cardiovascular events. 4,5 Improvement in endothelial function induced by exercise training may contribute to these beneficial effects in cardiovascular risk. 6 Data in animals and humans suggest that endothelial shear stress is a key stimulus responsible for vascular adaptation in both artery function and remodeling in response to repeated exercise. 7-9 However, little is known about the exact shear stress stimulus responsible for the beneficial exercise-induced vascular adaptations.We demonstrated recently that shear rate (SR) in the brachial artery differs markedly in response to different types of exercise. For example, handgrip exercise induces an elevation in antegrade SR, whereas cycling results in large increases in antegrade and retrograde blood flow and SR. 10 The observation that different types of shear are present during various types of exercise raises the question of whether different patterns of SR are associated with different vascular adaptations. Although studies performed in vitro and in animals have suggested that different shear patterns induce different cellular events, varying between proatherogenic and antiatherogenic changes, 9 limited information is available in humans.The primary purpose of our study was to examine whether different flow and shear stimuli mediate different acute changes in vascular function, examined using flow-mediated dilation (FMD), a largely endothelium-and NO-dependent stimulus, 11-15 in humans. We measured brachial artery FMD before and after 3 different 30-minute interventions (recumbent leg cycling, forearm heating, and handgrip exercise) that were associated with significantly different SR patterns. To further elaborate on the impact of blood flow and SR patterns on endothelial function, we simultaneously performed identical interventions in the contralateral limb of each subject, which had a cuff inflated to 60 mm Hg throughout the intervention period to attenuate shear levels within subjects.

Abstract-Changes in arterial shear stress induce functional and structural vasculature adaptations. Recent studies indicate that substantial retrograde flow and shear can occur through human conduit arteries. In animals, retrograde shear is associated with atherogenic effects. The aim of this study was to examine the impact of incremental levels of retrograde shear on endothelial function in vivo. On 3 separate days, we examined bilateral brachial artery flow-mediated dilation, an index of NO-mediated endothelial function, in healthy men (24Ϯ3 years) before and after a 30-minute intervention consisting of cuff inflation to 25, 50, or 75 mm Hg. Cuff inflations resulted in "dose"-dependent increases in retrograde shear rate, compared with the noncuffed arm, within subjects (PϽ0.001). Flow-mediated dilation in the cuffed arm did not change in response to the 25-mm Hg stimulus but decreased significantly after both the 50-and 75-mm Hg interventions (PϽ0.05). The decrease in flow-mediated dilation after the 75-mm Hg intervention was significantly larger than that observed after a 50-mm Hg intervention (Pϭ0.03). In the noncuffed arm, no changes in shear rate or flow-mediated dilation were observed. These results demonstrate that an increase in retrograde shear rate induces a dose-dependent attenuation of endothelial function in humans. This finding contributes to our understanding regarding the possible detrimental effects of retrograde shear rate in vivo. More recent studies indicate that changes in shear stress on the endothelial cell membrane are a key stimulus for adaptation in both vascular function and remodeling. 2-6 Elevation in endothelial shear stress, such as that present during exercise, is a key stimulus to express antiatherogenic genes (eg, endothelial NO synthase) 7 and decrease proatherogenic genes (eg, endothelin 1). 8 Importantly, these changes in gene expression are associated with enhanced endothelial function in vivo. 9,10 Although changes in shear can clearly transduce beneficial arterial adaptations, it is also apparent from studies performed in vitro and in animals that oscillatory shear stress, characterized by high levels of retrograde shear, can increase the expression of proatherogenic, and decreases antiatherogenic, genes. 11 For example, oscillatory shear increases endothelin 1 expression 12 and adhesion molecules 13,14 and enhances the release of superoxide 15 and expression of reactive oxygen species-producing enzymes (ie, NADPH oxidase) 16,17 but decreases endothelial NO synthase expression. 16,17 However, the impact of changing retrograde shear stress has never been examined in humans.The primary purpose of this study was to examine the impact of different magnitudes of retrograde shear stress on endothelial function in humans. To this end, we simultaneously examined brachial artery endothelial function in both arms of healthy subjects before and after 30-minute exposure to stepwise increases in retrograde shear induced by cuff inflation on 1 forearm to 25, 50, or 75 mm Hg. In this wa...