Oxidative Stress Contributes to Microvascular Endothelial Dysfunction in Humans with Major Depressive Disorder

Vascular dysfunction is evident in humans with major depressive disorder (MDD); however, the specific molecular mediators remain unclear. In rodent models of depression, oxidative stress‐induced reductions in nitric oxide (NO) bioavailability contribute to impaired endothelium‐dependent vasodilation. We hypothesized that 1) markers of oxidant stress expression and activity would be increased in adults with MDD compared to healthy control (HC) subjects (in vitro), 2) NO‐dependent vasodilation would be attenuated in adults with MDD (in vivo), and 3) acute in vivo scavenging of reactive oxygen species (ROS) would improve endothelial function in MDD. 6 HC (36±9 yrs) and 5 adults with MDD (33±8 yrs) participated; MDD subjects had clinically significant depressive symptoms, classified according to the Center for Epidemiologic Studies Depression Scale (CES‐D score 34±3). NADPH oxidase expression (p47phox subunit; Western blot analysis) and total ROS production (fluorometric assay) were quantified in forearm cutaneous homogenates. Red blood cell flux (laser Doppler flowmetry) was measured during graded intradermal microdialysis infusion of acetylcholine alone (ACh; 10−8‐10−1M) and during co‐infusion with the non‐specific NO synthase inhibitor NG‐nitro‐L‐arginine methyl ester (L‐NAME; 20mM) and the non‐specific antioxidant ascorbate (AA; 20mM). Cutaneous vascular conductance (CVC=flux/mean arterial pressure) was expressed as a percentage of maximum (sodium nitroprusside; local heat to 43°C). NADPH oxidase expression and total ROS production were increased in adults with MDD (P<0.05 for both). ACh‐induced vasodilation was blunted in adults with MDD (96±2 HC v. 72±5 MDD %CVCmax; P<0.05); however, there were no group differences in cutaneous vasodilation during NO synthase inhibition (46±4 HC v. 49±6 MDD %CVCmax; P=0.7). AA infusion improved ACh‐induced vasodilation in MDD (72±5 ACh v. 89±10 AA %CVCmax; P=0.11). These data demonstrate impaired NO‐mediated endothelium‐dependent vasodilation in MDD and further suggest a biochemical mechanism and functional role for oxidant stress in mediating vascular dysfunction in MDD.Support or Funding InformationHL120471‐03 and HL093238‐06