In order to bring you the best possible user experience, this site uses Javascript. If you are seeing this message, it is likely that the Javascript option in your browser is disabled. For optimal viewing of this site, please ensure that Javascript is enabled for your browser.
Did you know that your browser is out of date? To get the best experience using our website we recommend that you upgrade to a newer version. Learn more.

Oxidative Stress Contributes to Microvascular Endothelial Dysfunction in Men and Women With Major Depressive Disorder

Edited by Olivia Manfrini & Edina Cenko

Vascular Tone, Permeability, Microcirculation
Cardiovascular Disease in Women
ESC Working Groups
Depression and Heart Disease

Oxidative Stress Contributes to Microvascular Endothelial Dysfunction in Men and Women With Major Depressive Disorder. Greaney JL et al. 2019

Summary of the Original Article


There is growing consensus for considering depression as a modifiable prognostic factor for coronary heart disease (CHD), and for the need of improved efforts towards better understanding, recognition and management thereof. Endothelial dysfunction is evident in major depressive disorder (MDD); but the specific molecular mechanisms underlying reductions in NO-mediated endothelial function in MDD remain incompletely understood [1]. Methods: Greaney et al analysed the role of oxidative stress in mediating microvascular endothelial dysfunction, including potential influences of sex, in MDD. The authors took an in vivo pharmacological approach using transdermal microdialysis to measure vascular function in 24 otherwise healthy, young adults with MDD (14 women; 18-23 years) and 20 healthy control (10 women; 19-30 years). Small microdialysis fibers was placed in the outer layers of the skin to infuse the endothelium-dependent vasodilator acetylcholine, alone or in combination with a nitric oxide (NO) synthase inhibitor (L-NAME), superoxide scavenger, NADPH oxidase inhibitor (apocynin), and endothelium-independent vasodilator sodium nitroprusside. The outcome measures were changes in blood flow (red cell flux) measured by laser Doppler flowmetry in response to drug infusion. Results: The authors found that endothelium-dependent dilation was blunted in MDD and negatively related to depressive symptom severity. Nonselective pharmacological inhibition of NOS attenuated ACh-induced dilation in healthy control, but not in MDD, indicating that a functional loss of NO-mediated dilation contributes to endothelial dysfunction in MDD. Interestingly, there were no sex differences in either NO-mediated endothelium-dependent dilation or endothelium-independent dilation, both in MDD and control. Finally, acute scavenging of superoxide or inhibition of NADPH oxidase improved NO-dependent dilation in MDD. Conclusion: The study demonstrated that oxidative stress-induced reductions in NO-dependent dilation, as well as alterations in vascular smooth muscle function, directly contribute to microvascular dysfunction in MDD otherwise healthy subjects.

Comments to the article

Major depression is a highly prevalent condition, affecting approximately 10% of the population and it has been consistently associated with increased risk of coronary heart disease (CHD). Experimental and epidemiological studies indicate that there is a bidirectional association between depression and CHD [1]. Mechanisms linking depression to CHD risk are complex, multifactorial, and still incompletely understood [1].

In this context, Greaney et al. conducted a very relevant study. On the one hand, they provided evidence of a bio-pathophysiological mechanism linking MDD to cardiovascular disease: oxidative stress, via reductions in NO-dependent mechanisms, directly contributes to microvascular dysfunction in otherwise healthy young adults with MDD. On the other hand, the study suggests that oxidative stress, specifically superoxide, is a potential therapeutic target for improving vascular function and reducing cardiovascular risk in adults with depression. Also, strategies targeting oxidative stress in the microvasculature may have therapeutic and preventative effects on the pathogenesis of depression itself.

In this regard, it should be noted that exercise training and Mediterranean diet preserves and improves endothelial function [6,7]. Therefore, in the management of subjects with MDD, these interventions should always be considered. Specifically, exercise has been consistently found to be efficacious for the treatment of depression, at least equivalent to the effects of SSRIs or psychotherapy [1]. Moreover, in patients with CHD, cardiac rehabilitation is highly effective in improving mental health, including depression, as well as physical health outcomes including subsequent CHD events and mortality [1].

Various studies support an inverse correlation between depressed mood and endothelial function, as measured by flow-mediated dilation (FMD) [1-3]. The relationship between depression and endothelial dysfunction is likely due to reduced endothelium-derived NO [3] as shown by lower FMD of brachial arteries and reduced NO bioavailability in subcutaneous microvessels in patients with depressed mood [1,4-5]. Moreover, acute mental stress in the laboratory induces transient endothelial dysfunction, as measured by FMD, which lasts up to 4 hours [8]. The study of Greaney et al adds an important finding on the relationship between endothelial dysfunction and the association depression-CHD. Young women are more likely to develop MDD than men and also suffer greater depressive symptom severity. But, premenopausal women have lower CHD risk than men [1]. The interaction among sex, MDD and CHD is currently unclear. However, in the present study sex does not appear to selectively modulate NO-dependent dilatory mechanisms in depression.

Finally, it should be highlighted that Greaney et al. also evaluated a subset of adults with MDD treated with a selective serotonin reuptake inhibitor (SSRI) for their depressive symptoms and that were in remission (n=8; 7 women; 19–37 years). They found that NO-mediated component of endothelium-dependent dilation was improved in SSRI-treated MDD adults. The observation is limited by the potential for SSRI treatment to directly influence vascular function, but it is consistent with other studies suggesting that patients whose depression improves with SSRIs may have better cardiac outcomes [1]. In this regard, we should keep in mind that some data suggest that SSRIs, like tricyclics, when used long-term may increase the risk of cardiac events and death [1]. These events are rare, however, whether effective and safe treatment of depression may improve CHD outcomes, and whether specific patient subgroups may benefit more from such treatments, requires further evaluation [1].

In conclusion, the study by Greaney et al. provides important new information on the pathophysiology linking MDD and CHD and represents a springboard for the design of future prospective clinical studies.


  1. Vaccarino V, Badimon L, Bremner JD, Cenko E, Cubedo J, Dorobantu M, Duncker DJ, Koller A, Manfrini O, Milicic D, Padro T, Pries AR, Quyyumi AA, Tousoulis D, Trifunovic D, Vasiljevic Z, de Wit C, Bugiardini R; ESC Scientific Document Group Reviewers. Depression and coronary heart disease: 2018 ESC position paper of the working group of coronary pathophysiology and microcirculation developed under the auspices of the ESC Committee for Practice Guidelines. Eur Heart J. 2019 Jan 28.
  2. Sherwood A, Hinderliter AL, Watkins LL, Waugh RA, Blumenthal JA. Impaired endothelial function in coronary heart disease patients with depressive symp- tomatology. J Am Coll Cardiol 2005;46:656–659.
  3. Pries AR, Badimon L, Bugiardini R, Camici PG, Dorobantu M, Duncker DJ, Escaned J, Koller A, Piek JJ, de Wit C. Coronary vascular regulation, remodel- ling, and collateralization: mechanisms and clinical implications on behalf of the working group on coronary pathophysiology and microcirculation. Eur Heart J 2015;36:3134–3146.
  4. Rajagopalan S, Brook R, Rubenfire M, Pitt E, Young E, Pitt B. Abnormal brachial artery flow-mediated vasodilation in young adults with major depression. Am J Cardiol 2001;88:196–198, A7.
  5. Greenstein AS, Paranthaman R, Burns A, Jackson A, Malik RA, Baldwin RC, Heagerty AM. Cerebrovascular damage in late-life depression is associated with structural and functional abnormalities of subcutaneous small arteries. Hypertension 2010;56:734–740.
  6. Hambrecht R, Wolf A, Gielen S, Linke A, Hofer J, Erbs S, Schoene N, Schuler G. Effect of exercise on coronary endothelial function in patients with coronary artery disease. N Engl J Med. 2000 Feb 17;342(7):454-60.
  7. Mattioli AV, Palmiero P, Manfrini O, Puddu PE, Nodari S, Dei Cas A, Mercuro G, Scrutinio D, Palermo P, Sciomer S, Di Francesco S, Novo G, Novo S, Pedretti RFE, Zito A, Parati G, Pedrinelli R, Farinetti A, Maiello M, Moscucci F, Tenaglia RL, Sucato V, Triggiani M, Cugusi L, Scicchitano P, Saba PS, Ciccone MM. Mediterranean diet impact on cardiovascular diseases: a narrative review. J Cardiovasc Med (Hagerstown). 2017 Dec;18(12):925-935.
  8. Ghiadoni L, Donald AE, Cropley M, Mullen MJ, Oakley G, Taylor M, O’Connor . G, Betteridge J, Klein N, Steptoe A, Deanfield JE. Mental stress induces transient endothelial dysfunction in humans. Circulation 2000;102:2473–2478.
The content of this article reflects the personal opinion of the author/s and is not necessarily the official position of the European Society of Cardiology.