Retrograde Flow and Shear Rate Acutely Impair Endothelial Function in Humans

Abstract

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...

Impact of 2‐Weeks Continuous Increase in Retrograde Shear Stress on Brachial Artery Vasomotor Function in Young and Older Men

“…In this manner, this study successfully introduced compression sleeves as a method to manipulate retrograde SR, both acutely and chronically in men in vivo. Although a nonsignificant increase was found in antegrade SR in both young and older men, the main observation was that we (in line with our previous work) successfully manipulated retrograde shear 2, 12, 39. Although we only explored the impact of the sleeve intervention on resting levels of retrograde shear, we are confident that increased levels of retrograde SR were also present during various activities of daily living.…”

“…As a logical follow‐up study from initial findings that acute elevation in retrograde shear induces impairment in endothelial function,2 this study aimed to assess the effect of chronic (ie, 2 weeks) manipulation of retrograde SR in humans in vivo. First, we successfully introduced a compression sleeve in young and older men, as a simple and easily applied tool to elevate resting retrograde SR in the brachial artery for 2 weeks.…”

“…In previous studies, we used pneumatic cuffs to manipulate retrograde shear acutely 2, 12. For chronic shear manipulation, however, blood pressure cuffs are impractical.…”

“…In contrast, elevation in retrograde shear stress may be potentially detrimental 2, 10, 11. For example, an inverse and dose‐dependent relationship is described between acute increases in retrograde shear rate (SR) and brachial artery endothelial function in young men 2, 12…”

Influence of sympathetic vasoconstrictor tone on conduit artery retrograde and oscillatory shear: Effects of habitual aerobic exercise in middle-aged and older adults

“…Shear stress demonstrates a typical pattern (i.e., antegrade and retrograde shear) in conduit arteries. Elevation in retrograde and oscillatory shear may have pro-atherogenic effects [1][2][3][4][5][6] . Aging causes increased retrograde shear and oscillatory shear in peripheral conduit arteries [7][8][9][10] .…”