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Psychosomatic Medicine:
doi: 10.1097/PSY.0000000000000062
Original Articles

Association Between Endothelial Dysfunction and Depression-Like Symptoms in Chronic Mild Stress Model of Depression

Bouzinova, Elena V. PhD; Norregaard, Rikke PhD; Boedtkjer, Donna M.B. PhD; Razgovorova, Irina A. MSc; Moeller, Anaïs M.J. BSc; Kudryavtseva, Olga PhD; Wiborg, Ove PhD; Aalkjaer, Christian DMSc; Matchkov, Vladimir V. DMSc

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Abstract

Objective: Cardiovascular diseases have high comorbidity with major depression. Endothelial dysfunction may explain the adverse cardiovascular outcome in depression; therefore, we analyzed it in vitro. In the chronic mild stress model, some rats develop depression-like symptoms (including “anhedonia”), whereas others are stress resilient.

Methods: After 8 weeks of chronic mild stress, anhedonic rats reduced their sucrose intake by 55% (7%), whereas resilient rats did not. Acetylcholine-induced endothelium-dependent relaxation of norepinephrine-preconstricted mesenteric arteries was analyzed in nonstressed, anhedonic, and resilient rat groups.

Results: Small resistance arteries from anhedonic rats were less sensitive to acetylcholine than those of the nonstressed and resilient groups (p = .029). Pathways of endothelium-dependent relaxation were altered in arteries from anhedonic rats. Nitric oxide (NO)–dependent relaxation and endothelial NO synthase expression were increased in arteries from anhedonic rats (0.235 [0.039] arbitrary units and 155.7% [8.15%]) compared with the nonstressed (0.135 [0.012] arbitrary units and 100.0% [8.08%]) and resilient (0.152 [0.018] arbitrary units and 108.1% [11.65%]) groups (p < .001 and p = .002, respectively). Inhibition of cyclooxygenase (COX) activity revealed increased COX-2–dependent relaxation in the anhedonic group. In contrast, endothelial NO synthase– and COX-independent relaxation to acetylcholine (endothelium-dependent hyperpolarization–like response) was reduced in anhedonic rats (p < .001). This was associated with decreased transcription of intermediate-conductance Ca2+-activated K+ channels.

Conclusions: Our findings demonstrate that depression-like symptoms are associated with reduced endothelium-dependent relaxation due to suppressed endothelium-dependent hyperpolarization–like relaxation despite up-regulation of the NO and COX-2–dependent pathways in rat mesenteric arteries. These changes could affect peripheral resistance and organ perfusion in major depression.

Copyright © 2014 by American Psychosomatic Society

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