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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

doi: 10.1097/PSY.0000000000000062
Original Articles

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.

From the Department of Clinical Medicine (E.V.B., R.N., O.W.), Aarhus University Hospital, Aarhus, Denmark; Department of Biomedicine (D.M.B.B., A.M.J.M., O.K., C.A.,V.V.M), MEMBRANES, Aarhus University, Aarhus, Denmark; and Department of General Physiology (I.A.R.), St Petersburg State University, St Petersburg, Russia.

Address correspondence and reprint requests to Vladimir V. Matchkov, DMSc, Department of Biomedicine, Aarhus University, Ole Worms Alle bygn. 4, 1163, Aarhus C 8000, Denmark. E-mail:

Received for publication September 10, 2013; revision received January 29, 2014.

Copyright © 2014 by American Psychosomatic Society
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