Oxidative Stress Contributes to Microvascular Endothelial Dysfunction in Men and Women With Major Depressive Disorder

Abstract

Rationale: In rodent models of depression, oxidative stress-induced reductions in nitric oxide (NO) bioavailability contribute to impaired endothelium-dependent dilation. Endothelial dysfunction is evident in Major Depressive Disorder (MDD); however, the molecular mediators remain undefined. Objective: We sought to translate preclinical findings to humans by testing the role of oxidative stress in mediating microvascular endothelial dysfunction, including potential modulatory influences of sex, in MDD. Methods and Results: Twenty-four treatment-naïve, otherwise healthy, young adults with MDD (14 women; 18-23 yrs) and twenty healthy adults (HC; 10 women; 19-30 yrs) participated. Red blood cell flux (laser Doppler flowmetry) was measured during graded intradermal microdialysis perfusion of the endothelium-dependent agonist acetylcholine, alone and in combination with an NO synthase inhibitor (L-NAME), a superoxide scavenger (Tempol), and an NADPH oxidase inhibitor (apocynin), as well as during perfusion of the endothelium-independent agonist sodium nitroprusside. Tissue oxidative stress markers (e.g., nitrotyrosine abundance, superoxide production) were also quantified. Endothelium-dependent dilation was blunted in MDD and mediated by reductions in NO-dependent dilation. Endothelium-independent dilation was likewise attenuated in MDD. In MDD, there were no sex differences in either NO-mediated endothelium-dependent dilation or endothelium-independent dilation. Acute scavenging of superoxide or inhibition of NADPH oxidase improved NO-dependent dilation in MDD. Expression and activity of oxidative stress markers were increased in MDD. In a subset of adults with MDD treated with a selective serotonin reuptake inhibitor for their depressive symptoms and in remission (n=8; 7 women; 19-37 yrs), NO-mediated endothelium-dependent dilation was preserved, but endothelium-independent dilation was impaired, compared to HC.

Analysis of cerebrovascular dysfunction caused by chronic social defeat in mice

“…Many factors might contribute to breakdown of BBB at the level of small cerebral vessels, including peripheral and/or central inflammation, oxidative stress, extracellular matrix degradation, and elevated blood pressure ( Low et al, 2019 ; Ungvari et al, 2017 ). Such factors are prevalent in hypertension, small vessel disease, and atherosclerosis ( Iadecola and Gottesman, 2019 ), and some are associated with psychological stress disorders ( Marsland et al, 2017 ; Schiavone et al, 2013 ) and depression ( Black et al, 2015 ; Greaney et al, 2019 ; Kohler et al, 2017 ; Salim, 2014 ). Endothelial cells, which line the blood vessel lumen, are the principal component of the BBB ( Blanchette and Daneman, 2015 ).…”

The Association Between Vascular Inflammation and Depressive Disorder. Causality, Biomarkers and Targeted Treatment

“…Deficits in FMD in peripheral blood vessels are associated with depression symptoms [27,87]. In fact, blunted FMD responses correlate both with the presence and the severity of depression symptoms [79,[88][89][90]. These results make FMD a useful biomarker for depression that is secondary to a vascular inflammatory disorder.…”

Overview of the Assessment of Endothelial Function in Humans

“…Laser speckle contrast imaging (LSCI) utilizes a widespread laser, forgoing a grid scanning process required in the previous techniques, allowing faster imaging ( 110 , 111 ). A range of stimuli can be used to stimulate the endothelium of the skin microvasculature as well, including PORH, local thermal hyperaemia, iontophoresis or transdermal application of acetylcholine, and microdialysis to introduce drugs of interest ( 109 , 112 , 113 ). Laser-based techniques have also been used in clinical use where assessment of microcirculation is warranted, such as in wound and burn assessments ( 114 ).…”