Endothelial dysfunction (ED) is the first pathophysiological step that produces atherosclerosis, which is responsible for ≈90% of all cardiovascular diseases. 1-4 ED is generally defined as the decrease in nitric oxide (NO) bio-availability within the endothelium, normally attributed to an increased endothelial oxidative stress. [1][2][3]5,6 In humans, early stages 7 and changes after interventions 8-10 of ED can be assessed non-invasively via flow-mediated dilation (FMD). [11][12][13][14][15] Briefly, FMD measures the dilatory capacity of a blood vessel, typically the brachial artery, which is exposed to a blood flow-induced stimulus (i.e. shear stress) elicited by reactive hyperemia. 12,13 Although FMD is recognized as a bioassay for ED, [11][12][13][14][15] with excellent clinical significance, 16,17 few studies have shown a relationship between FMD and endothelial oxidative stress in humans. 18 FMD is based on two physiological principles: (1) blood flow-induced shear stress activates the endothelium to produce NO; and (2) NO elicits vascular dilation via relaxation of vascular smooth muscle. 12,14 When there is an increased endothelial oxidative stress, endothelial NO synthase (eNOS) is uncoupled, producing a decrease in NO production and bioavailability. 5,6,19 Thus, an increased endothelial oxidative stress should decrease endothelial reactivity to shear stress, which will negatively impact FMD.Accordingly, the purpose of the present study was to determine if FMD is associated with endothelial oxidative Abstract Flow-mediated dilation (FMD) is recognized as a non-invasive endothelial function bioassay. However, FMD's relationship with endothelial cell oxidative stress in humans is yet to be determined. Here, we sought to determine if FMD was associated with endothelial nitric oxide synthase (eNOS) and endothelial oxidative stress in humans. Twenty-seven apparently healthy young men (26.5±5.9 years) underwent brachial artery FMD testing and endothelial cell biopsy from a forearm vein. Non-normalized FMD (%) and three different brachial artery FMD normalizations were performed: (1) peak shear rate (%/SR); (2) area under the SR curve until peak dilation (%/AUC); and (3) AUC 30 seconds before peak dilation (%/AUC30). Immunofluorescence quantification was used to assess eNOS expression and nitrotyrosine (NT), a criterion marker of endothelial oxidative stress. Values for eNOS and NT expression were reported as a ratio of endothelial cell to human umbilical vein endothelial cell average pixel intensity. NT expression was significantly correlated with FMD normalized by AUC30 (r = −0.402, p<0.05). Other FMD normalizations and non-normalized FMD were not significantly correlated with NT expression (r range = −0.364 to −0.142, all p>0.05). There were no significant correlations between eNOS expression and normalized and non-normalized FMD (r range = −0.168 to −0.066, all p>0.05). In conclusion, brachial artery FMD is associated with venous endothelial cell oxidative stress. However, this association is observed onl...

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