Greaney JL, et al. - Researchers performed this study on 24 treatment-naïve, otherwise healthy, young adults with Major Depressive Disorder (MDD) (14 women; 18-23 yrs) and 20 healthy adults (HC; 10 women; 19-30 yrs), to unveil the molecular mediators of endothelial dysfunction in MDD, focusing mainly on the role of oxidative stress and sex as possible mediators. They measured red blood cell flux (laser Doppler flowmetry) during graded intradermal microdialysis perfusion of the endothelium-dependent agonist as well as during perfusion of the endothelium-independent agonist sodium nitroprusside, and also quantified tissue oxidative stress markers. They observed a direct contribution of oxidative stress-induced reductions in nitric oxide (NO)-dependent dilation, as well as alterations in vascular smooth muscle function, to microvascular dysfunction in MDD. In either NO-mediated endothelium-dependent dilation or endothelium-independent dilation, no sex differences were seen in MDD. In MDD, an improvement in NO-dependent dilation was observed by acute scavenging of superoxide or inhibition of NADPH oxidase. Also, increased expression and activity of oxidative stress markers were detected in MDD. Overall, cardiovascular risk in MDD may be reduced by targeting vascular oxidative stress.