Depressive behavior and vascular dysfunction: a link between clinical depression and vascular disease?

Area of Science:

• Cardiovascular Research
• Neuroscience
• Endocrinology

Background:

• Chronic stress and depression are linked to peripheral vascular disease.
• An established mouse model of chronic stress/depressive symptoms was used to investigate this link.
• Unpredictable chronic mild stress (UCMS) exacerbates depressive behaviors in male mice.

Purpose of the Study:

• To examine the impact of chronic stress on vascular function and identify underlying mechanisms.
• To assess the relationship between stress, vascular reactivity, and markers of metabolic and inflammatory disease.
• To determine if insulin resistance, inflammation, or hypertension predict vascular dysfunction in a chronic stress model.

Main Methods:

• Male mice underwent 8 weeks of unpredictable chronic mild stress (UCMS).
• Vascular ring studies assessed endothelium-dependent and independent dilation and constrictor responses.
• Nitric oxide synthase (NOS) and cyclooxygenase (COX) inhibition, along with catalase, were used to probe signaling pathways.
• Arterial nitric oxide (NO) and hydrogen peroxide (H2O2) production were measured.
• Insulin resistance, inflammation (TNF-alpha, IL-1beta, C-reactive peptide), and hypertension were assessed.

Main Results:

• UCMS attenuated endothelium-dependent dilation (methacholine) but not endothelium-independent dilation or constrictor responses.
• UCMS reduced arterial NO production and increased H2O2 production.
• NOS inhibition affected UCMS mice differently than controls, while COX inhibition impacted both groups.
• A significant dilation remained in UCMS mice after combined NOS/COX blockade, abolished by catalase, indicating a role for reactive oxygen species.
• While UCMS mice showed increased insulin resistance and inflammation, these factors, along with hypertension, were not robust predictors of vascular dysfunction, except in the most severe cases.

Conclusions:

• Chronic stress impairs vascular endothelial function, partly through reduced NO bioavailability and increased oxidative stress.
• Insulin resistance, inflammation, and hypertension do not consistently predict the severity of vascular dysfunction in this chronic stress model.
• Unidentified mechanisms likely play a significant role in mediating poor vascular outcomes associated with chronic stress.