Temporal Evolution of Brain Inflammation in the Bilateral Common Carotid Artery Stenosis Model of Chronic Cerebral Hypoperfusion

Abstract

Chronic cerebral hypoperfusion is a major contributor to vascular cognitive impairment and dementia, primarily through its disruption of white matter integrity and promotion of neuroinflammatory cascades. The bilateral common carotid artery stenosis (BCAS) model has emerged as the predominant experimental approach for studying the effects of chronic cerebral hypoperfusion, particularly in aging-relevant contexts. This review synthesizes current knowledge of inflammatory responses in the BCAS model, with an emphasis on their temporal progression and functional consequences. We begin by outlining the clinical burden of hypoperfusion, the rationale for BCAS, and the hemodynamic phases it produces. We then examine early neurovascular unit dysfunction, including coordinated responses among endothelial cells, pericytes, and astrocytes. These changes converge on blood-brain barrier compromise, followed by loss of tight junctions, activation of matrix metalloproteinases, and routes of leukocyte entry via venules and the choroid plexus. Inflammatory mediators such as IL-1β, TNF-α, and IL-6 amplify injury, while microglia transition from acute responders to chronic effectors of white matter damage. Although many reports have catalogued inflammatory changes, causal tests remain sparse. Few studies manipulate specific cytokines, border-associated macrophages, or temporally restricted cellular pathways, leaving unvalidated the checkpoints that govern the shift from adaptive responses (angiogenesis, gliosis, debris clearance) to maladaptive, self-sustaining inflammation. Clarifying the temporal dynamics of neuroinflammation in BCAS is critical for defining therapeutic windows and developing strategies that preserve compensatory mechanisms while preventing chronic pathology. Future research should prioritize cell-specific and time-resolved approaches to identify mechanistic checkpoints that can be targeted therapeutically to mitigate hypoperfusion-driven cognitive decline.