Mechanisms of peripheral vascular dysfunction in human depression

Major depressive disorder (MDD) is a major global health concern and is directly linked to the development of cardiovascular disease (CVD). Accumulating evidence from humans and rodent models indicates that vascular dysfunction plays a pathogenic role in MDD-CVD comorbidity. Mounting evidence in rodent models of depression indicates that reductions in nitric oxide (NO) bioavailability, secondary to increases in oxidant stress and inflammation, are a key mechanism in depression-induced endothelial dysfunction. Studies in both rodents and humans suggest a critical role for the nuclear transcription factor nuclear factor-kB (NFkB) in the pro-oxidant/pro-inflammatory-linked suppression of endothelium-dependent vasodilation in cardiovascular pathology. However, the extent to which vascular oxidant stress, as well as the upregulation of systems supporting the production of reactive oxygen species (ROS), directly contribute to endothelial dysfunction in otherwise healthy adults with MDD remains unclear. Using an interdisciplinary translational approach, this proposal will comprehensively examine the mechanisms mediating endothelial dysfunction in adults with MDD, and their modulation by chronic selective serotonin reuptake inhibitor (SSRI) treatment, and will test the overall hypothesis that MDD-induced vascular endothelial dysfunction is mediated by two interrelated oxidant stress signaling pathways: 1) directly via increased endogenous ROS production and 2) in parallel by NFkB transcriptional activation-induced increases in ROS signaling. In Aim 1, we will examine the mechanistic role of oxidant stress in mediating impaired NO-dependent endothelial function in adults with MDD. In Aim 2, we will examine the role of NFkB activation in mediating oxidant stress-induced impairments in NO-dependent endothelial function in adults with MDD. These studies will directly translate findings from rodent models to human depression. In addition, potential follow-up studies have been identified that will be critical elements in the applicant's career progression and will foster her development as an independent investigator. Considering the prevalence of MDD and, separately, CVD in modern societies, elucidating the mechanistic underpinnings of vascular endothelial dysfunction in MDD will likely provide novel therapeutic targets to alleviate the CVD risk in depressed adults, thus advancing the mission of the AHA to reduce CVD-related mortality. (AHA Program: Scientist Development Grant)