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POINT-COUNTERPOINT
School of Physical and Health Education
Queen's University
Kingston, Ontario, Canada
E-mail: mt29{at}post.queensu.ca
The phenomenon of flow-mediated dilation (FMD) relevant to this debate describes the vasodilation in a conduit vessel in response to elevations in flow-associated shear stress. Nitric oxide (NO) is thought to play a key role in vascular health due to its established vasoprotective characteristics (for review, see Ref. 8). Because NO is one of the substances produced by the vascular endothelium in response to elevations in flow-associated shear stress (2), considerable clinical interest has focused on noninvasive assessment of FMD for evaluating NO-specific endothelial function in humans.
Celermajer et. al (4) in 1992 were the first to examine FMD induced by elevated forearm conduit vessel blood flow velocity after ischemia-induced downstream vasodilation [reactive hyperemia (RH)] to assess FMD in groups at risk for atherosclerosis and observed a blunted response. Since then, numerous studies assessing FMD in various pathologies and in response to various therapeutic interventions have been conducted. A blunting of the FMD response relative to healthy controls is taken to represent endothelial dysfunction. With regard to NO, Joannides et al. (17) in 1995 were the first to examine the NO contribution to RH-induced FMD in humans and found that NO blockade completely abolished FMD. Their concluding statement was "...the present investigation demonstrates that NO is essential for flow mediated dilatation of human radial arteries in vivo. Thus this test can be used as a reliable noninvasive estimate of the capacity of human endothelial cells to release NO..." The common clinical view now, as stated in the recent technique report by the International Brachial Artery Reactivity Task Force in 2002 (6), is that vascular endothelial NO production accounts for FMD, and the primary citation supporting this is the above-mentioned Joannides et al. (17) paper.
Unfortunately, the history of FMD research represents a clinically driven desire to evaluate endothelial function that has bypassed careful mechanistic dissection of FMD in vivo in humans. The issue here is whether FMD specifically reflects NO-mediated endothelial function. A careful mechanistic exploration of FMD reveals three critical characteristics that seriously question the current dogma that FMD represents NO-mediated endothelial function: 1) the nature of the shear stimulus affects the vasoregulatory mechanisms evoked, 2) shear stress acts as a stimulus for endothelial release of vasoconstrictors, and 3) elevated sympathetic activation, characteristic of numerous pathologies in which endothelial dysfunction is observed, can blunt the FMD response.
Shear stimulus characteristics determine FMD mechanisms.
It is well established that there are a number of signaling pathways activated with an increase in shear stress and at least three vasodilators who's production increases have been identified (NO, prostacyclin, endothelium-derived hypopolarizing factor) (3). Therefore, a common stimulus (shear stress) exists for the simultaneous activation of a number of vasoregulatory mechanisms.
Mullen et al. (22) investigated the impact of the duration of the shear stress stimulus on the NO dependence of the FMD response in the radial artery. They found that only the FMD in response to a brief shear stress stimulus was reduced by L-NMMA blockade of NO. In contrast, the FMD response to more sustained stimuli caused by release of 15 min ischemia, skin warming, or distal acetylcholine infusion was unaffected, indicating an NO-independent mechanism(s). Of note, similar blunting of FMD with L-NMMA infusion reported by Joannides et al. (17) can be explained by the L-NMMA infusion-induced attenuation of the reactive hyperemia in their study in healthy humans. In other words, blunted FMD with L-NMMA infusion could be due to a blunted stimulus, not necessarily a reduction in NO-mediated dilation (25). Both the identity and dynamics (when the role of NO ends and that of another vasodilator(s) begins) of the mechanism(s) that is responsible for the FMD in response to a more prolonged elevation in shear stress are therefore still unknown.
The relevance of considering shear stress stimulus characteristics beyond the simple 5-min ischemia-induced transient shear elevation is clear when we consider the relevance of this stimulus for FMD in the coronary arteries. Coronary artery FMD is recognized as a critical response for adequate perfusion of cardiac muscle during increased work of the heart (26). The nature of the shear stress stimulus for these vessels is not reflected by the 5 min RH stimulus. Shiode et al. (26) demonstrated that shear stress-induced coronary artery dilation is not dependent on NO. Zeiher et al. (30) demonstrated that impaired coronary artery vasodilation in exercise is associated with myocardial ischemia. This implies that improvements in coronary artery FMD to a sustained shear stress stimulus may attenuate myocardial ischemia. Therefore, FMD in response to sustained shear stress may constitute a critical component of endothelial function for which NO may not be obligatory.
Shear stimulus evokes endothelin release.
In addition to release of vasodilators in response to elevations in shear stress, it has been demonstrated that endothelin release can also be stimulated (21, 28, 29). Endothelin is a potent vasoconstrictor. Thus alterations in the responsiveness of endothelin release by the vascular endothelium would be expected to influence FMD. Of particular relevance to this point is the observation by Berger et al. (1) that blockade of endothelin-A receptors improves FMD in patients with chronic heart failure. Indeed, these authors also point out the importance of considering that vascular tone is the net result of interaction between simultaneously active vasoregulatory factors.
Sympathetic activation can account for blunted FMD in numerous pathologies.
Emerging evidence of sympathetic modulation of FMD highlights the consequence of a lack of careful dissection of multiple mechanisms that interact to determine FMD. It is well established that hyperactivation of the sympathetic nervous system is implicated in cardiovascular outcomes (5, 9, 27). Many of the pathologies associated with endothelial dysfunction as evidenced by blunted FMD also demonstrate sympathetic hyperactivity. For example blunted FMD and elevated sympathetic tone is characteristic of aging (7, 11), obstructive sleep apnea (16, 23), heart failure (14, 18), and hypertension (13, 20) to name a few. In addition, nonpathological states associated with elevated sympathetic activation also demonstrate blunted FMD. These include diurnal variations in FMD (24) and mental stress, particularly in persons characterized by high levels of hostility (12).
Recently, Hijmering et al. (15) examined the effect of lower body negative pressure-induced sympathetic elevation in healthy humans. Their results clearly demonstrate that elevations in sympathetic activation result in considerable blunting of FMD. In addition, interventions that have been demonstrated to improve FMD in sleep apnea (continuous positive airway pressure) (16), aging (10), cardiovascular disease (ACE inhibitors) (19) also either reduce sympathetic activity or have sympathicolytic effects. Taken together, these observations demonstrate that the common assumption that FMD represents NO-mediated endothelial function is particularly misleading in understanding endothelial function and interpreting the impact of therapeutic interventions in conditions where elevated sympathetic activation also exists.
In summary, FMD as an "assay" of NO-mediated endothelial function relies on a shear stress stimulus that has a highly complex signal transduction cascade evoking multiple vasoactive mechanisms. FMD in response to many shear stress profiles is not sensitive to NO blockade. In addition, there is unquestionable evidence that sympathetic activation influences the FMD response, and this activation is characteristic of many of the pathologies and altered states in which blunted FMD is observed. Finally, treatment of these pathologies often involves sympathicolytic or sympathetic activation-reducing agents/interventions. Thus we believe the current dogma that FMD reflects NO-mediated endothelial function is in error.
REFERENCES
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