INTRODUCTION
Atherosclerosis and its complications such as acute coronary syndromes are leading causes of death worldwide. Acute psychosocial stress exposure is known to be a major trigger for the onset of acute coronary syndromes, even in patients with state-of-the-art medical treatment. However, how acute psychosocial stress rapidly drives plaque destabilization causing acute coronary syndromes is poorly understood and consequently, specific treatment, although urgently needed, is lacking.
METHODS & RESULTS
We subjected atherosclerotic mice (ApoE-/- mice on a high cholesterol diet for 8 weeks) to psychosocial stress by immobilizing mice in restrainers for 3h. Using flow cytometry, we found that stress elevated atherosclerotic plaque leukocyte numbers over non-stressed counterparts (neutrophils: 1400* vs 4677*/cells per aorta; Ly6Chigh monocytes: 1183* vs. 2216*/cells per aorta; macrophages: 6006* vs. 17573*/cells per aorta; non-stressed vs. stress, *p<0.05)). In accord, histological analyses revealed a stress-induced increase in plaque leukocyte numbers (CD11b+ area per total plaque area in stressed mice compared to non-stressed mice (64,5% vs. 56,3%, p<0.05)). When testing how stress expanded plaque leukocytes, we found that stress increased uptake of blood leukocytes into plaques in adoptive transfer experiments. Next, we investigated how stress promotes plaque leukocyte recruitment and performed RNA sequencing in FACS (fluorescence-activated cell sorting)-isolated plaque endothelial cells (EC) from stressed and non-stressed mice. Here we found that stress modulates EC phenotypes as displayed by 533 differentially expressed genes of which 335 were up- and 198 were down-regulated (log2FoldChange+1.5, adjusted p<0.05) upon stress. Next, we investigated how stress modulates plaque ECs and found that stress activates local sympathetic innervation leading to a surplus release of norepinephrine. Using systemic (via 6-OHDA injection) and local (via surgical denervation) norepinephrine depletion strategies, we dampened leukocyte recruitment into atherosclerotic plaques under stress conditions.
CONCLUSION
Acute psychosocial stress promotes the influx of blood inflammatory leukocytes into plaques through the activation of ECs. In this context, local norepinephrine release is involved in mediating stress-induced EC activation. In ongoing experiments, we will further investigate intervention strategies to dampen stress-induced leukocyte recruitment.