Mechanisms of Endothelial Dysfunction in Young Adults with Major Depressive Disorder: Influence of Sex

Major Depressive Disorder (MDD) is associated with endothelial dysfunction, a primary causative event in the development of cardiovascular disease. In rodents, depression‐induced endothelial dysfunction is modulated by sex, with females demonstrating less severe impairments than males owing to increased nitric oxide (NO) bioavailability, secondary to greater antioxidant defense mechanisms. This relative preservation of endothelial function in female rodents occurs despite an increased behavioral susceptibility to depressive‐like behaviors. Women of reproductive age are more than twice as likely to suffer from MDD; however, the influence of sex on the molecular mediators of endothelial dysfunction in humans with MDD remains unexplored. We hypothesized that endothelial dysfunction would be less severe in otherwise healthy young women with MDD compared to men with MDD due to increased nitric oxide (NO) bioavailability, mediated by greater antioxidant mechanisms. Twenty healthy adults (HC; 10 men; 22±1 yr) and 23 adults with MDD (9 men; 20±0.3 yr; PHQ‐9 score 12±1) participated. Red blood cell flux (laser Doppler flowmetry) was measured during graded intradermal microdialysis perfusion of the endothelium‐dependent agonist acetylcholine (ACh; 10−10–10−1 M) alone and with the co‐perfusion of the NO synthase inhibitor NG‐nitro‐L‐arginine methyl ester (L‐NAME; 20 mM), the superoxide dismutase mimetic Tempol (TEM; 10 μM), or the NADPH oxidase inhibitor apocynin (APO; 100 μM). Endothelium‐dependent dilation (EDD) was expressed as a percentage of maximum cutaneous vascular conductance (CVC=flux·mmHg−1). Tissue oxidant stress markers were quantified in cutaneous tissue homogenates (Western blot). As expected, EDD was blunted in MDD and mediated by reductions in NO bioavailability and increases in oxidative stress. There were no sex differences in EDD in either HC (87±6% men vs. 93±9% women; P=0.07) or MDD (79±10% men vs. 76±9% women; P=0.70). In MDD, the NO‐dependent portion of the vasodilatory response was also not different between men and women (14±5% men vs. 16±5% women; P=0.78). Further, pharmacological scavenging of superoxide or inhibition of NADPH oxidase improved EDD to a similar extent men and women with MDD (TEM: 81±7% men vs. 95±3% women, P=0.10; APO: 91±3% men vs. 88±5% women, P=0.65). Nitrotyrosine and NADPH oxidase (p47phox) expression were increased in MDD but not different between sexes (both P>0.05). Although these data confirm significant vascular impairments in MDD via oxidant stress mechanisms, these preliminary findings suggest that sex does not modulate the mechanisms mediating endothelial dysfunction in otherwise healthy young adults with MDD.Support or Funding InformationHL133414This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.