title: Depressive behavior and vascular dysfunction: a link between clinical depression and vascular disease?
abstract: As chronic stress and depression have become recognized as significant risk factors for peripheral vascular disease in patients with no prior history of vasculopathy, we interrogated this relationship utilizing an established mouse model of chronic stress/depressive symptoms from behavioral research. Male mice were exposed to 8 wk of unpredictable chronic mild stress (UCMS; e.g., wet bedding, predator sound/smell, random disruption of light/dark cycle), with indexes of depressive behavior (coat status, grooming, and mobility) becoming exacerbated vs. controls. In vascular rings, constrictor (phenylephrine) and endothelium-independent dilator (sodium nitroprusside) responses were not different between groups, although endothelium-dependent dilation (methacholine) was attenuated with UCMS. Nitric oxide synthase (NOS) inhibition was without effect in UCMS but nearly abolished reactivity in controls, while cyclooxygenase inhibition blunted dilation in both. Combined blockade abolished reactivity in controls, although a significant dilation remained in UCMS that was abolished by catalase. Arterial NO production was attenuated by UCMS, although H2O2 production was increased. UCMS mice demonstrated an increased, although variable, insulin resistance and inflammation. However, while UCMS-induced vascular impairments were consistent, the predictive power of aggregate plasma levels of insulin, TNF-alpha, IL-1beta, and C-reactive peptide were limited. However, when separated into tertiles with regard to vascular outcomes, insulin resistance and hypertension were predictive of the most severe vascular impairments. Taken together, these data suggest that aggregate insulin resistance, inflammation, and hypertension in UCMS mice are not robust predictors of vascular dysfunction, suggesting that unidentified mechanisms may be superior predictors of poor vascular outcomes in this model.
authors.affiliation: Center for Cardiovascular and Respiratory Sciences, Department of Community Medicine, West Virginia University School of Medicine, Morgantown, WV 26505, USA.
authors.forename: Alexandre C
authors.initials: AC
authors.lastname: d'Audiffret
authors.forename: Stephanie J
authors.initials: SJ
authors.lastname: Frisbee
authors.forename: Phoebe A
authors.initials: PA
authors.lastname: Stapleton
authors.forename: Adam G
authors.initials: AG
authors.lastname: Goodwill
authors.forename: Elsa
authors.initials: E
authors.lastname: Isingrini
authors.forename: Jefferson C
authors.initials: JC
authors.lastname: Frisbee
mesh_terms: D000818:Animals; D001011:Aorta / Q000187:drug effects / Q000378:metabolism / Q000503:physiopathology*; D001522:Behavior, Animal; D015415:Biomarkers / Q000097:blood; D002908:Chronic Disease; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology; D003863:Depression / Q000150:complications* / Q000378:metabolism / Q000503:physiopathology; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D006861:Hydrogen Peroxide / Q000378:metabolism; D006973:Hypertension / Q000503:physiopathology / Q000523:psychology; D007249:Inflammation / Q000503:physiopathology / Q000523:psychology; D018836:Inflammation Mediators / Q000097:blood; D007333:Insulin Resistance; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D009569:Nitric Oxide / Q000378:metabolism; D052250:Nitric Oxide Synthase Type III / Q000037:antagonists & inhibitors / Q000378:metabolism; D012307:Risk Factors; D012720:Severity of Illness Index; D013315:Stress, Psychological / Q000150:complications* / Q000378:metabolism / Q000503:physiopathology; D013997:Time Factors; D014652:Vascular Diseases / Q000378:metabolism / Q000503:physiopathology / Q000523:psychology*; D014661:Vasoconstriction / Q000187:drug effects; D014662:Vasoconstrictor Agents / Q000494:pharmacology; D014664:Vasodilation / Q000187:drug effects; D014665:Vasodilator Agents / Q000494:pharmacology
chemical_list: D015415:Biomarkers; D016861:Cyclooxygenase Inhibitors; D018836:Inflammation Mediators; D014662:Vasoconstrictor Agents; D014665:Vasodilator Agents; D009569:Nitric Oxide; D006861:Hydrogen Peroxide; D052250:Nitric Oxide Synthase Type III; C496315:Nos3 protein, mouse