Analysis of cerebrovascular dysfunction caused by chronic social defeat in mice

• Published in: Brain, behavior, and immunity Vol. 88; pp. 735 - 747
• Main Authors: Lehmann, Michael L., Poffenberger, Chelsie N., Elkahloun, Abdel G., Herkenham, Miles
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier Inc 01.08.2020
• Subjects: Angiogenesis; Animals; Blood-Brain Barrier; Brain - blood supply; Cerebrovasculature; Depression; Endothelia; Endothelial Cells; Fibrinogen; Inflammation; Leukocyte; Male; Mice; Mice, Inbred C57BL; Neuroimmune; Psychosocial stress; Social Defeat; Stress, Psychological; Endothelia; Angiogenesis; Blood-brain barrier; Leukocyte; Neuroimmune; Fibrinogen; Psychosocial stress; Cerebrovasculature; Depression; Inflammation
• ISSN: 0889-1591; 1090-2139
• DOI: 10.1016/j.bbi.2020.05.030

•Chronic social defeat caused behavioral deficits and blood–brain barrier breaks.•Breaks showed tiny bleeds, fibrinogen deposition, and angiogenesis markers.•Brain endothelial cells were isolated for analysis at gene transcriptional level.•Stressed endothelial cells engaged vascular injury, growth, and repair programs.•These programs are also seen in hypertension, cardiovascular disease, and aging. Psychological stress and affective disorders are clinically associated with hypertension and vascular disease, but the biological links between the conditions have not been fully explored. To examine this relationship, we used chronic social defeat (CSD) stress, which produces anxiety-like and depressive-like behavioral declines in susceptible mice. In such mice, CSD also produces cerebrovascular microbleeds in scattered locations. Here, we showed further evidence of vascular pathology and blood–brain barrier breakdown by visualizing plasma immunoglobulins and erythrocytes within the parenchyma and perivascular spaces of CSD brains. To further characterize the impact of stress on the cerebrovasculature, brain endothelial cells (bECs) were isolated, and global gene expression profiles were generated. Bioinformatic analysis of CSD-induced transcriptional changes in bECs showed enrichment in pathways that delineate the vascular response to injury. These pathways followed a temporal sequence of inflammation, oxidative stress, growth factor signaling, and wound healing (i.e., platelet aggregation, hemostasis, fibrinogen deposition, and angiogenesis). Immunohistochemical staining for markers of fibrinogen deposition and angiogenesis confirmed the existence of the markers at the sites of vascular disruptions. Recovery after CSD cessation was marked by recruitment of leukocytes perhaps participating in vascular repair. The data suggest that co-morbidity of affective disorders and vascular diseases may be attributed in part to a common link in altered endothelial cell function.