Angiopoietin‐1/Tie‐2 signal after focal traumatic brain injury is potentiated by BQ788, an ETB receptor antagonist, in the mouse cerebrum: Involvement in recovery of blood–brain barrier function

Angiopoietin‐1, an angiogenic factor, stabilizes brain microvessels through Tie‐2 receptor tyrosine kinase. In traumatic brain injury, blood–brain barrier (BBB) disruption is an aggravating factor that induces brain edema and neuroinflammation. We previously showed that BQ788, an endothelin ETB receptor antagonist, promoted recovery of BBB function after lateral fluid percussion injury (FPI) in mice. To clarify the mechanisms underlying BBB recovery mediated by BQ788, we examined the involvements of the angiopoietin‐1/Tie‐2 signal. When angiopoietin‐1 production and Tie‐2 phosphorylation were assayed by quantitative reverse transcription polymerase chain reaction and western blotting, increased angiopoietin‐1 production and Tie‐2 phosphorylation were observed in 7–10 days after FPI in the mouse cerebrum, whereas no significant effects were obtained at 5 days. When BQ788 (15 nmol/day, i.c.v.) were administered in 2–5 days after FPI, increased angiopoietin‐1 production and Tie‐2 phosphorylation were observed. Immunohistochemical observations showed that brain microvessels and astrocytes contained angiopoietin‐1 after FPI, and brain microvessels also contained phosphorylated Tie‐2. Treatment with endothelin‐1 (100 nM) decreased angiopoietin‐1 production in cultured astrocytes and the effect was inhibited by BQ788 (1 μM). Five days after FPI, increased extravasation of Evans blue dye accompanied by reduction in claudin‐5, occludin, and zonula occludens‐1 proteins were observed in mouse cerebrum while these effects of FPI were reduced by BQ788 and exogenous angiopoietin‐1 (1 μg/day, i.c.v.). The effects of BQ788 were inhibited by co‐administration of a Tie‐2 kinase inhibitor (40 nmol/day, i.c.v.). These results suggest that BQ788 administration after traumatic brain injury promotes recovery of BBB function through activation of the angiopoietin‐1/Tie‐2 signal. The mechanisms underlying the BBB function recovery induced by BQ788, an endothelin ETB receptor antagonist, were examined in a mouse traumatic brain injury (TBI) model. In this model, BQ788 increased angiopoietin‐1 (ANG‐1) expression and phosphorylation of Tie‐2, which was accompanied by recovery of BBB function. These results suggest that activation of the angiopoietin‐1/Tie‐2 signal underlies the ability of BQ788 to recover BBB function.