Depression is associated with a doubled risk for cardiovascular disease and patients with circulatory disorders often develop a severe depression. Mechanisms underlying both pathologies in the developed state are similar: dysfunctions of the hypothalamic-pituitary-adrenal axis and the autonomic nervous system, an activation of the renin-angiotensin-aldosterone system and pro-inflammatory cytokines, as well as cardiovascular dysregulations. All these factors are capable for inducing both depression and changes in structure and function of the heart and blood vessels thereby creating a malignant cycle which usually leads to the chronic diseases (Fig. 1). Research on these mechanisms is complicated and often impossible in humans, but an animal model of depression provides opportunities for it. A Chronic Mild Stress (CMS) model of depression in rats is established in our group at the TNU at the Aarhus University. The model resembles closely the pathology in human population. The CMS model utilizes finding from epidemiological study about crucial role of environmental factors, mainly stressful live events, in the etiology of depression. The CMS paradigm is built on the chronic exposure to unpredictable mild stressors of small laboratory animals. The behavioural changes observed in this model are consistent with depression symptoms, e.g. abnormal physical activity and an inability to experience pleasure from normally pleasurable stimuli – anhedonia, shown by a reduction in the consumption of sucrose solution in a sucrose consumption test (SCT), where animals are exposed to a bottle of palatable sucrose solution once a week during 1 h. Anhedonia-like behaviour is defined as the reduction in sucrose intake for more than 30% compare to baseline (before CMS). Importantly, not all rats subjected to CMS develop anhedonia. The model demonstrates differentiated response to CMS and some animals are resilient to the CMS paradigm (fall in SCT no more than 10%), mirroring gradual stress coping abilities of humans (for review (1).Using the model we have shown that the low quality of maternal care, in early life, increases the susceptibility to stress exposure in adulthood. Our results indicate that high, as opposed to low maternal care, predisposed rats to a differential stress-coping ability. Moreover, low maternal care offspring had lower weight gain and lower locomotion, with no additive effect of stress. Subchronic exposure to chronic mild stress induced an increase in faecal corticosterone metabolites, which was only significant in rats from low maternal care dams (2). Rats responded to CMS with anhedonic behaviour have an increased level of corticosterone (CORT) and two peaks in diurnal CORT secretion (3). Decrease in expression of glucocorticoid receptors (GR) in different areas of hippocampus was observed in anhedonic rats compare to control and resilient rats (p<0.001 by 2-way ANOVA) after 4 weeks of CMS by semiquantitative analysis of protein expression detected by GR M-20 antibody. Similar to the systemic CORT concentration, effect of CMS on GR expression was not distinguishable after 8 weeks of CMS. Multi-Plex cytokine detection system revealed 14 products different between CMS groups and/or time of CMS. Results were subjected to principle component analysis. If to consider the positive loadings on both factors as an activation of immune response, than control rats demonstrate negative activation at 4 and 8 weeks of CMS. In contrast, resilient rats demonstrate strong activation of immune response. Anhedonic rats demonstrate increase in the activation of immune system between 4 and 8 weeks of CMS. We found in myograph studies the extended peripheral effect of increased systemic CORT. Depression-like symptoms were associated with increased neuronal monoamine reuptake in small arteries, which compensates for stress-induced suppression of CORT-sensitive extra-neuronal reuptake. These changes are due to an increased expression of neuronal noradrenaline transporter and a decreased expression of extra-neuronal organic cation co-transporter 2 (4). Activation of immune system and increased concentration of pro-inflammatory cytokines in circulation are known factors affecting the endothelial functions. Depression-like symptoms are associated with reduced endothelium-dependent relaxation due to suppressed EDH-like relaxation despite the up-regulation of the NO and COX-2-dependent pathways in small arteries. We suggest that this suppression of relaxation might be another reason for elevated vasoconstriction and thus TPR in depression (5).Increased heart rate in anhedonic rats and no changes in arterial blood pressure between three groups suggest that rats with depression-like behaviour compensate the decrease in cardiac output with an increase in total peripheral resistance (4).