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To investigate the role of astroglial water channel aquaporin-4 (AQP4) in maintaining blood–brain barrier integrity, structure and permeability of the brain microvessels were investigated in adult AQP4 knockout mice. Altered ultrastructure of brain microvessels, including open tight junctions and swollen perivascular astrocytic endfeet, were frequently observed in the AQP4 null mice. Likewise, AQP4 deficiency significantly downregulated expression of glial fibrillary acidic protein in perivascular processes of astrocytes. Furthermore, the horseradish peroxidase analysis demonstrated hyperpermeability of the blood–brain barrier in AQP4 knockout mice. These findings provide direct evidence that AQP4 is essential for the maintenance of blood–brain barrier integrity.