Astrocyte–blood–brain barrier crosstalk in cerebral small vessel disease: linking barrier dysfunction to neurovascular failure

Abstract

Cerebral small vessel disease (CSVD) is a heterogeneous group of disorders involving the cerebral microvasculature and is a major cause of stroke and vascular cognitive impairment. The role of blood–brain barrier (BBB) dysfunction in CSVD is now recognized as a key pathological process; however, conventional vascular risk factors do not fully explain its initiation, progression, or clinical heterogeneity. Astrocyte–BBB crosstalk has been implicated in endothelial dysfunction, pericyte injury, and vascular remodeling, and the mechanisms by which early barrier instability progresses to neurovascular failure remain poorly understood. This review highlights astrocytes as active regulators of BBB integrity and neurovascular unit homeostasis. Astrocytic endfeet support endothelial junctions, regulate basement membrane structure, and maintain water and ion homeostasis, perivascular exchange, inflammatory regulation, and neurovascular coupling. Astrocytes may shift from a homeostatic to a reactive state following chronic hypoperfusion, inflammatory stress, metabolic injury, or APOE4-related vulnerability, leading to increased inflammatory signaling, loss of AQP4 and Kir4.1 polarization, basement membrane remodeling, and pericyte dysfunction. Barrier instability persists, resulting in impaired glymphatic clearance, disrupted cerebral blood flow regulation, and white matter and cognitive impairment. We hypothesize a key mechanistic link between BBB dysfunction and neurovascular failure in CSVD related to disrupted astrocyte–BBB crosstalk. However, much of the current evidence is derived from animal models and in vitro systems, and direct human data–particularly from longitudinal imaging and biomarker cohorts–remain limited. Future work should integrate imaging, biomarkers, and stratified therapies to improve early detection and restore astrocytic endfoot polarity and BBB homeostasis.