Connecting the dots--establishing causality between chronic stress, depression, and cardiovascular disease.

IN THIS ISSUE, Stanley et al. (16a) reported sex differences of unpredictable chronic mild stress (UCMS) on vascular function. They found that BALBc/J mice subjected to UCMS [reported to induce depression in rodents (9, 10)] demonstrate impairment in endothelium-dependent dilation and that the symptoms of stress/depression were more severe in females than males but that endothelium-dependent dilation to acetylcholine or methacholine was more impaired in males. As to the mechanisms underlying endothelial dysfunction, production of thromboxane A2 was elevated and that of prostacyclin was decreased (based on stable metabolite levels). Free nitric oxide levels were also decreased, which was interpreted as due to scavenging by elevated levels of reactive oxygen species. The authors also associated the blunted endothelium-dependent dilation with the cytokines, tumor necrosis factor-alpha (TNF), and monocyte chemoattractant protein-1 (MCP1). We pose four rhetorical questions that both highlight and impact the scientific message of Stanley et al. What is the significance of stress and depression in cardiovascular disease? The association between stress, particularly depression, and cardiovascular disease is fairly recent with some of the earlier reports being published in the 1980s (3, 6, 18, 20); however the importance of depression as a risk factor in cardiovascular diseases has recently become more widely heralded (8, 11, 13, 19, 21–24). Despite these associations, causality has not been established. This is where the present study makes an important step, by demonstrating that in mice unpredictable chronic mild stress leads to endothelial dysfunction. Although endothelial dysfunction is not vascular disease, it is the first step in a sequence of pathological developments that can evolve to vascular disease. Importantly, the endothelial dysfunction reported by the authors was not the result of hypertension, because hypertension was not found. Rather it was through unpredictable chronic mild stress itself. This is noteworthy, because if the animals had developed hypertension, endothelial dysfunction would have been expected (14, 16). What is known about the mechanisms by which stress and depression impact cardiovascular disease? The answer is simple: little! The literature even has evidence supporting the hypothesis that vascular dysfunction can lead to depression and cognitive deficits (1, 2, 5) in addition to depression causing the vascular pathology. A literature analysis concluded that the relationship between vascular disease and depression cannot be explained by current established risk factors and that factors such as endothelial dysfunction and cytokines must be considered (17). Along this line, a recent report suggests that endothelial dysfunction in UCMS is due to the production of TNF, because the dysfunction was rescued by administration of the TNF neutralizing antibody infliximab (7). The study of Stanley et al. not only corroborates this particular finding but extends the observation to include a potential role of monocyte chemoattractant protein-1 (MCP-1), reactive oxygen species, thromboxane A2, and decreased production of prostacyclin. However, there remain many gaps in our knowledge. For example, what is the mechanism for increased expression/ production of TNF ? Are inflammatory cells involved and if so how are they activated? And, what is the role of MCP-1 in this process? Typically MCP-1 attracts monocytes to areas of injury, but in this case, where is the injury and what tissue(s) is (are) expressing the cytokine? Obviously there are many gaps in our understanding of the links between stress and depression to cardiovascular disease. The contribution by Stanley et al. helps in understanding the connections. What is the basis for the difference in sex, and does this apply in humans? One of the provocative observations in the study by Stanley et al. was the sex-related difference in response to UCMS: females demonstrated a greater response to UCMS than males in terms of coat status, anhedonia, delayed grooming, cortisol levels, and oxidative stress (nitrotyrosine), but males had a larger deficit in endothelial function. The mechanisms underlying this difference remain unresolved. First, this effect was likely mediated via an effect on or by the endothelium. Supporting this were observations that contraction and relaxation of arteries to agonists acting directly on smooth muscle (phenylephrine and nitroprusside) were virtually equivalent among the different groups. Females also produced more NO and prostacyclin and less thromboxane A2 than males. However, it is worth noting that constriction of arterioles to phenylephrine was augmented in male mice (compared with females) subjected to UCMS, so there may be a smooth muscle component, although this effect seems small. Interestingly, the authors also observed that TNF and MCP-1 concentrations were higher in females than males subjected to UCMS, yet endothelial dysfunction was, as mentioned, greater in males. This provocative observation was not further interrogated, suggesting where further research is needed. Perhaps such a response to stress also provides insight into many of the sex-related differences in the occurrence of depression, in which there is a higher incidence in women than men (15), and even in premenopausal women (4), who are at lower risk for heart and vascular disease than men. An interesting clinical correlate is provided by Hamano et al. (12), in which the effects of depression were more strongly correlated with stroke in men than in women. Is this the human clinical counterpart of Stanley et al.—that a more depressed, stressed female mouse would have better endothelial function than a male depressed mouse? Of course this question has not been answered, but it appears that the authors’ model and study may have parallels to the human condition. Address for reprint requests and other correspondence: W. M. Chilian, Dept. of Integrative Medical Sciences, Northeast Ohio Medical Univ., 4209 State Route 44, Rootstown, OH (e-mail: [email protected]). J Appl Physiol 117: 957–958, 2014; doi:10.1152/japplphysiol.00856.2014. Invited Editorial