Flow-mediated dilation stimulated by sustained increases in shear stress: a useful tool for assessing endothelial function in humans?

Abstract

Investigations of human conduit artery endothelial function via flow-mediated vasodilation (FMD) have largely been restricted to the reactive hyperemia (RH) technique, wherein a transient increase in shear stress after the release of limb occlusion stimulates upstream conduit artery vasodilation (RH-FMD). FMD can also be assessed in response to sustained increases in shear stress [sustained stimulus (SS)-FMD], most often created with limb heating or exercise. Exercise in particular creates a physiologically relevant stimulus because shear stress increases, and FMD occurs, during typical day-to-day activity. Several studies have identified that various conditions and acute interventions have a disparate impact on RH-FMD versus SS-FMD, sometimes with only the latter demonstrating impairment. Indeed, evidence suggests that transient (RH) and sustained (SS) shear stress stimuli may be transduced via different signaling pathways, and, as such, SS-FMD and RH-FMD appear to offer unique insights regarding endothelial function. The present review describes the techniques used to assess SS-FMD and summarizes the evidence regarding 1) SS-FMD as an index of endothelial function in humans, highlighting comparisons with RH-FMD, and 2) potential differences in shear stress transduction and vasodilator production stimulated by transient versus sustained shear stress stimuli. The evidence suggests that SS-FMD is a useful tool to assess endothelial function and that further research is required to characterize the mechanisms involved and its association with long-term cardiovascular outcomes. NEW & NOTEWORTHY Sustained increases in peripheral conduit artery shear stress, created via distal skin heating or exercise, provide a physiologically relevant stimulus for flow-mediated dilation (FMD). Sustained stimulus FMD and FMD stimulated by transient, reactive hyperemia-induced increases in shear stress provide distinct assessments of conduit artery endothelial function.

Keywords: endothelium; exercise; flow-mediated dilation; nitric oxide; shear stress.

Fig. 1.

Schematic representation of reactive hyperemia flow-mediated vasodilation (RH-FMD; top) and handgrip exercise flow-mediated vasodilation [sustained stimulus (SS)-FMD; bottom] in a protocol designed to target a single shear rate. The solid lines represent the stimulus (shear stress); the dashed lines represent the response (vasodilation). The shear stress stimulus for RH-FMD is large and transient compared with a more gradual onset, sustained increase in shear stress with exercise-induced SS-FMD. The ultrasound velocity trace (middle) shows that the shear rate is entirely antegrade during RH, whereas it is mildly oscillatory during handgrip exercise because of contraction-induced impedance to flow. Increases in diameter correspond to the shear stress stimuli, with RH evoking a generally parabolic increase and decrease in diameter, whereas SS produces a slower, sustained increase in diameter.

Fig. 2.

Synthesis of investigations implementing rhythmic handgrip exercise sustained shear stimulus flow-mediated vasodilation (SS-FMD). Studies included measured brachial artery diameter and maximal voluntary contraction (A) or mean shear rate (B) in young, healthy participants. Data are presented as means with SE bars and include 12 studies.

Fig. 3.

Summary schematic of sustained shear stimulus flow-mediated vasodilation (SS-FMD) compared with reactive hyperemia flow-mediated vasodilation (RH-FMD). The results from cell culture and isolated vessel studies suggest that transient and sustained shear stress are differentially transduced by the endothelium. Transient increases in shear stress are thought to activate endothelial nitric oxide (NO) synthase (eNOS) and produce NO via a Ca²⁺-dependent pathway, whereas sustained increases in shear stress activate eNOS in a distinct, Ca²⁺-independent pathway (28, 53). Hypothetically extrapolated to in vivo conduit artery studies, RH-FMD is depicted as reflecting primary recruitment of the Ca²⁺-dependent eNOS activation pathway. SS-FMD is depicted as initially eliciting Ca²⁺-dependent eNOS activation (if the initial increase in shear is abrupt); however, the prolonged stimulus is identified as relying to a greater extent on Ca²⁺-independent eNOS activation. There is evidence for involvement of endothelium-derived hyperpolarizing factors, namely epoxyeicosatrienoic acids (EETs), in both RH-FMD and SS-FMD (5, 26). Reactive oxygen species appear to contribute to SS-FMD (72), and H₂O₂ may be the responsible signaling molecule. There is emerging evidence that endothelin-1 (ET-1) binding to endothelial ET-1 type B (ET_B) receptors contributes to SS-FMD by facilitating ET-1 uptake; when ET-1 binds to ET type A (ET_A) receptors, vasoconstriction is promoted (4). Distinct RH-FMD versus SS-FMD pathways may be differentially affected by certain interventions and cardiovascular risk factors [smoking, type 1 diabetes mellitus (T1DM), hypercholesterolemia, high-fat meal, and acute mental stress], thereby providing a theoretical basis for the disparate findings of SS-FMD and RH-FMD. There is a need to incorporate both SS-FMD and RH-FMD in future studies to further understand the mechanistic and functional distinctions of SS-FMD and RH-FMD in the context of endothelial function.