Brain microvascular endothelial cells: Beyond a barrier.

The blood-brain barrier (BBB) has long been regarded as a passive, protective filter for the brain. This review re-evaluates the role of brain microvascular endothelial cells (BMECs)-from viewing them as static structural components to recognizing them as dynamic immunoregulatory sentinels within the neurovascular unit. BMECs actively sense inflammatory and pathogenic signals through pattern recognition receptors, integrate competing pathways such as Wnt/β-catenin and NF-κB, and make context-dependent decisions to balance barrier integrity with immune defense. In response to activation, they orchestrate neuroimmune communication by secreting chemokines, modulating adhesion molecules, and facilitating immune cell trafficking. Dysregulation of these functions contributes to the pathogenesis of various central nervous system disorders, including stroke, Alzheimer's disease, and multiple sclerosis, where BMECs dysfunction drives neuroinflammation and barrier breakdown. Further progress is required to resolve endothelial heterogeneity, develop precise tools for barrier function assessment, and define targeted interventions that modulate the immunoregulatory functions of BMECs in order to explain the mechanistic heterogeneity observed in neurological disorders. These efforts will deepen our understanding of the BBB's role in physiology and pathology, offering new strategies for the prevention and treatment of neurological diseases, and highlight BMECs as active participants in brain immunity and potential therapeutic targets.