Chronic psychological stress induces vascular inflammation in rabbits

Abstract

Psychological stress is associated with a systemic inflammatory response. It is unclear, however, whether psychological stress contributes to vascular inflammation. Here, we examined the effects of unpredictable chronic mild stress (UCMS) on vascular inflammation in rabbits. One hundred rabbits were randomly divided into control and stress groups. UCMS was induced by a set of defined adverse conditions applied in a shuffled order for 4, 8, 12, or 16 weeks, and rabbits were killed 24 h after the end of the UCMS protocol. Expression of different inflammatory molecules was analyzed by real-time polymerase chain reaction, immunohistochemistry, or enzyme-linked immunosorbent assay. UCMS resulted in depression-like behaviors, decreased body weight gain, and hypertension with no significant effects on serum lipids. Aortic mRNA and protein expression for tumor necrosis factor-α (TNF-α), C-reactive protein (CRP), monocyte chemoattractant protein-1 (MCP-1), macrophage migration inhibitory factor, and expression of intercellular adhesion molecule-1 (ICAM-1) protein were increased. UCMS increased circulating concentrations of corticosterone, TNF-α, and CRP throughout. Moreover, stress downregulated the expression of endothelial nitric oxide synthase. At 16 weeks of UCMS, macrophage infiltration and lipid accumulation in the subendothelial space were detected in the aorta. In cultured murine vascular smooth muscle cells, treatment with serum from stressed rabbits significantly increased phosphorylation of p38 and c-Jun N-terminal kinase (JNK), and upregulated expression of MCP-1 and ICAM-1 mRNAs, in which the effect was blunted by a TNF-α neutralizing antibody or p38 and JNK inhibitors. Our results indicate that chronic psychological stress induces vascular inflammation via TNF-α and p38/JNK pathways, which may contribute to the development of atherosclerosis.

Chronic stress impacts the cardiovascular system: animal models and clinical outcomes

“…However, treatment of depression is not always accompanied by reduced levels of proinflammatory cytokines (210,361). In an attempt to a show causal relationship between stress-induced cytokine changes and cardiovascular complications, Lu et al (204) evaluated the effect of an unpredictable chronic mild stress protocol on vascular inflammation in rabbits. In this experiment, unpredictable chronic mild stress induced hypertension (without changes in lipid profiles) along with depression-like behavior.…”

Endothelial Dysfunction Induced by Chronic Psychological Stress: A Risk Factor for Atherosclerosis

“…The chronic unpredictable stress increased plasma TNF-α levels and its expression in rabbits' aorta, as well as infiltration of macrophage and lipid accumulation in the sub-endothelial space. Such characteristics are similar to initial stages of atherosclerosis [57]. Vascular smooth muscle cells treated with serum from stressed rabbits showed increase in the expression of MCP-1, ICAM-1, phosphorylation of mitogenactivated protein kinase (MAPKs), MAPKp38 and c-jun N-terminal kinase (JNK) [57].…”

“…Such characteristics are similar to initial stages of atherosclerosis [57]. Vascular smooth muscle cells treated with serum from stressed rabbits showed increase in the expression of MCP-1, ICAM-1, phosphorylation of mitogenactivated protein kinase (MAPKs), MAPKp38 and c-jun N-terminal kinase (JNK) [57]. The MAPKs signaling pathway regulates the processes of cell differentiation and proliferation, protein expression to leukocyte adhesion and it is involved in the atherosclerotic process.…”

“…The MAPKs signaling pathway regulates the processes of cell differentiation and proliferation, protein expression to leukocyte adhesion and it is involved in the atherosclerotic process. Pro-inflammatory effects induced by chronic stress were partially blocked by anti-TNF-α antibody, MAPKp38 and JNK inhibitors, suggesting that TNF-α, MAPKp38 and JNK activation can play a critical role in the pro-inflammatory and pro-atherogenic effects after chronic stress [57].…”

“…Chronic stress plays a critical role in the induction of vascular inflammation and progression of atherosclerotic lesions [54][55][56][57]. The chronic unpredictable stress increased plasma TNF-α levels and its expression in rabbits' aorta, as well as infiltration of macrophage and lipid accumulation in the sub-endothelial space.…”