Analysis of cerebrovascular dysfunction caused by chronic social defeat in mice

Abstract

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.

The semantics of microglia activation: neuroinflammation, homeostasis, and stress

“…These results suggest that development of the BM-chimera model enabled extravasation of myeloid cells into the brain following RSD [ 157 , 159 , 162 – 164 ]. Despite limited evidence for leukocyte trafficking in the brain, these studies did find that RSD caused a decline in BBB integrity [ 157 , 165 ]. These stress-induced changes in the BBB were associated with vascular remodeling and the passage of signaling peptides, indicating that more subtle processes are involved during stress as compared to neuroinflammation [ 163 , 165 ].…”

“…Despite limited evidence for leukocyte trafficking in the brain, these studies did find that RSD caused a decline in BBB integrity [ 157 , 165 ]. These stress-induced changes in the BBB were associated with vascular remodeling and the passage of signaling peptides, indicating that more subtle processes are involved during stress as compared to neuroinflammation [ 163 , 165 ]. It is important to point out that accumulation of peripheral myeloid cells and loss of BBB integrity has been primarily observed in the RSD model.…”

Impact of stress and hypertension on the cerebrovasculature

“…Chronic social defeat stress was shown to be associated with enrichment in pathways that delineate the vascular response to injury. These pathways followed a temporal sequence of immune responses manifested in microglial activity, inflammation, oxidative stress, growth factor signaling, and wound healing (i.e., platelet aggregation, hemostasis, fibrinogen deposition, and angiogenesis) resulting in cerebrovascular microbleeds in scattered locations, vascular pathology and blood-brain barrier breakdown visualized by plasma immunoglobulins and erythrocytes within the parenchyma and perivascular spaces of the mice brains [22,23].…”

Psychosocial Risk Factors, Noncommunicable Diseases, and Animal Models for COVID-19

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