Protection from vascular dysfunction in female rats with chronic stress and depressive symptoms

Abstract

The increasing prevalence and severity of clinical depression are strongly correlated with vascular disease risk, creating a comorbid condition with poor outcomes but demonstrating a sexual disparity whereby female subjects are at lower risk than male subjects for subsequent cardiovascular events. To determine the potential mechanisms responsible for this protection against stress/depression-induced vasculopathy in female subjects, we exposed male, intact female, and ovariectomized (OVX) female lean Zucker rats to the unpredictable chronic mild stress (UCMS) model for 8 wk and determined depressive symptom severity, vascular reactivity in ex vivo aortic rings and middle cerebral arteries (MCA), and the profile of major metabolites regulating vascular tone. While all groups exhibited severe depressive behaviors from UCMS, severity was significantly greater in female rats than male or OVX female rats. In all groups, endothelium-dependent dilation was depressed in aortic rings and MCAs, although myogenic activation and vascular (MCA) stiffness were not impacted. Higher-resolution results from pharmacological and biochemical assays suggested that vasoactive metabolite profiles were better maintained in female rats with normal gonadal sex steroids than male or OVX female rats, despite increased depressive symptom severity (i.e., higher nitric oxide and prostacyclin and lower HO and thromboxane A levels). These results suggest that female rats exhibit more severe depressive behaviors with UCMS but are partially protected from the vasculopathy that afflicts male rats and female rats lacking normal sex hormone profiles. Determining how female sex hormones afford partial vascular protection from chronic stress and depression is a necessary step for addressing the burden of these conditions on cardiovascular health. NEW & NOTEWORTHY This study used a translationally relevant model for chronic stress and elevated depressive symptoms to determine how these factors impact conduit and resistance arteriolar function in otherwise healthy rats. While chronic stress leads to an impaired vascular reactivity associated with elevated oxidant stress, inflammation, and reduced metabolite levels, we demonstrated partial protection from vascular dysfunction in female rats with normal sex hormone profiles compared with male or ovariectomized female rats.

Increased circulating microparticles in streptozotocin‐induced diabetes propagate inflammation contributing to microvascular dysfunction

“…Most of the data presented here were derived from female rats. Although oestrogen has been shown to be protective in certain diseases (Brooks et al 2018b) and beneficial in human health in general, reduced or abolished female protection has been reported in diabetic patients (McCollum et al 2005;Kalyani et al 2014), diabetic rats (He P, Xia X, LaPenna KB & Zhang Y; in press), and in animals with preexisting metabolic diseases (Brooks et al 2018a). In this study, we also found no significant differences in plasma MP concentrations between STZ-induced male and female diabetic rats (Fig.…”

“…Although oestrogen has been shown to be protective in certain diseases (Brooks et al . b ) and beneficial in human health in general, reduced or abolished female protection has been reported in diabetic patients (McCollum et al . ; Kalyani et al .…”

“…The plasma MPs used for the above characterizations were from female rats. Oestrogen has been shown to be protective in certain diseases (Brooks et al 2018b). The gender difference in plasma MPs under STZ-induced diabetic conditions were evaluated in another 16 age-matched male and female rats 2 weeks after STZ injection.…”

Short‐ and long‐term administration of the non‐steroidal mineralocorticoid receptor antagonist finerenone opposes metabolic syndrome‐related cardio‐renal dysfunction

“…Finally, it should be noted that, although not studied, gender/sex hormones might influence finerenone's cardiac and vascular responses to NO and other endothelial autocoids in Zucker fa/fa rats, as observed with other drugs used to reduce cardiovascular risk . Indeed, with pre‐existing metabolic syndrome, female lean Zucker rats are partially protected from the vasculopathy observed in male and ovariectomized female rats, while pre‐existing metabolic syndrome per se provokes impairment of the vasodilator responses to NO and/or prostacyclin; however, whether this will impact finerenone's cardiovascular effects remains to be determined.…”

Prefrontal Cortex Regulates Chronic Stress-Induced Cardiovascular Susceptibility

“…As depressioncardiovascular co-morbidity has twice the prevalence in females (Möller-Leimkühler, 2007;Tobet et al, 2013), it is important to consider sex-specific regulation. Interestingly, a recent study investigating vascular function in female rodents after chronic stress actually found that ovarian hormones protect against stress-induced arterial dysfunction (Brooks et al, 2018). Comparing the neural basis of pathological responses in males and females would likely yield a better understanding of the disproportionate female impact of mood disorder-cardiovascular co-morbidity.…”