Protective effect of sex on chronic stress- and depressive behavior-induced vascular dysfunction in BALB/cJ mice
Shyla C Stanley1, Steven D Brooks1, Joshua T Butcher1
1Center for Cardiovascular and Respiratory Sciences, West Virginia University Health Sciences Center, Morgantown, West Virginia Departments of Physiology and Pharmacology, West Virginia University Health Sciences Center, Morgantown, West Virginia.
Insights
Chronic stress worsens depression and cardiovascular disease (CVD) risk. While female mice show more severe stress behaviors, they exhibit blunted vasculopathy, suggesting better tolerance to oxidative stress and inflammation compared to males.
Area of Science:
- Neuroscience
- Cardiovascular Biology
- Stress Research
Background:
- Chronic stress is linked to depression and cardiovascular disease (CVD).
- Sex disparities exist, with premenopausal women experiencing more severe depressive symptoms but lower CVD risk.
- The differential impact of sex on stress-induced vascular dysfunction remains unclear.
Purpose of the Study:
- To investigate the sex-specific effects of unpredictable chronic mild stress (UCMS) on vascular function in male and female mice.
- To compare depressive behaviors and cardiovascular responses between sexes under chronic stress conditions.
Main Methods:
- An 8-week unpredictable chronic mild stress (UCMS) protocol was applied to male and female mice.
- Vascular reactivity (endothelium-dependent and -independent dilation) was assessed in conduit arteries and arterioles.
- Plasma cortisol levels, depressive symptom severity, reactive oxygen species (ROS), and systemic inflammation markers were measured.
Main Results:
- UCMS elevated plasma cortisol and depressive symptoms in both sexes, more severely in females.
- Male mice showed impaired endothelium-dependent dilation, reduced nitric oxide bioavailability, and increased ROS and inflammation.
- Female mice displayed blunted vascular reactivity alterations despite more severe depressive symptoms, indicating better tolerance to ROS and inflammation.
Conclusions:
- Female mice are more susceptible to stress-induced depressive behaviors but show relative protection against stress-induced vasculopathy compared to males.
- Improved tolerance to elevated reactive oxygen species and systemic inflammation may underlie the blunted vascular dysfunction in females.
- These findings highlight sex-specific mechanisms in the stress-depression-cardiovascular disease axis.
Abstract:
The presence of chronic, unresolvable stresses leads to negative health outcomes, including development of clinical depression/depressive disorders, with outcome severity being correlated with depressive symptom severity. One of the major outcomes associated with chronic stress and depression is the development of cardiovascular disease (CVD) and an elevated CVD risk profile. However, in epidemiological research, sex disparities are evident, with premenopausal women suffering from depressive symptoms more acutely than men, but also demonstrating a relative protection from the onset of CVD. Given this, we investigated the differential effect of sex on conduit artery and resistance arteriolar function in male and female mice following 8 wk of an unpredictable chronic mild stress (UCMS) protocol. In males, plasma cortisol and depressive symptom severity (e.g., coat status, anhedonia, delayed grooming) were elevated by UCMS. Endothelium-dependent dilation to methacholine/acetylcholine was impaired in conduit arteries and skeletal muscle arterioles, suggesting a severe loss of nitric oxide bioavailability and increased production of thromboxane A2 vs. prostaglandin I2 associated with elevated reactive oxygen species (ROS) and an increased level of systemic inflammation. Endothelium-independent dilation was intact. In females, depressive symptoms and plasma cortisol increases were more severe than in males, although alterations to vascular reactivity were blunted, including the effects of elevated ROS and inflammation on dilator responses. These results suggest that compared with males, female rats are more susceptible to chronic stress in terms of the severity of depressive behaviors, but that the subsequent development of vasculopathy is blunted owing to an improved ability to tolerate elevated ROS and systemic inflammatory stress.
