Impaired blood-brain barrier function in angiotensinogen-deficient mice

Astrocytes in the central nervous system have physiologically important roles in the response to brain injury(1,2). Brain damage results in disruption of the blood-brain barrier (BBB), producing detachment of astrocyte endfeet from endothelial cells(3). The resultant leakage of serum proteins from loosened tight junctions between endothelial cells produces brain edema. At the same time, reactive astrocytes migrate to the injured area, where they proliferate and produce extracellular matrix(4-6), thereby reconstituting the BBB. As astrocytes are known to express angiotensinogen(7,8), which is the precursor of angiotensins (Al to AIV), we have investigated a possible functional contribution of angiotensinogen or one of its metabolites to BBB reconstitution. The astrocytes of angiotensinogen knockout mice had very attenuated expression of glial fibrially acidic protein and decreased laminin production in response to cold injury, and ultimately incomplete reconstitution of impaired BBB function. Although these abnormalities were rescued by administration of All or AIV, the restoration of BBB function was not inhibited by All type 1 and 2 receptor antagonists. These findings provide evidence that astrocytes with angiotensins are required for functional maintenance of the BBB.