Angiopoietin-1 as a Candidate Molecule for Vasoprotection Against Hemorrhagic Transformation after Treatment with Tissue Plasminogen Activator (P05.235)

Abstract

Objective: To determine the effect of focal cerebral ischemia and tissue plasminogen activator (tPA) thrombolysis on the expression of angiopoietin-1 (Ang-1) in the blood-brain barrier (BBB). Background The use of tPA might cause hemorrhagic transformation (HT), especially when tPA is administered beyond the therapeutic time window. We previously showed that inhibition of the vascular endothelial growth factor (VEGF) signaling pathway attenuates HT after tPA thrombolysis. However, whether HT after tPA thrombolysis is related to the alteration of the signaling of Ang-1, which potentially reduces VEGF-induced BBB damage, remains unknown. Design/Methods: Male Sprague–Dawley rats subjected to thromboembolic focal cerebral ischemia were assigned to a permanent ischemia group and groups treated with tPA (10 mg/kg) at 1 h or 4 h after ischemia induction. The effects of focal cerebral ischemia and tPA thrombolysis on the expression and localization of Ang-1 in the BBB were evaluated by immunohistochemical and immunoblot analyses. Results: At 24 h after ischemia, the group receiving tPA treatment at 4 h after ischemia showed matrix metalloprotease-9 activation, BBB component degradation, and HT. In the sham group, Ang-1 expression was observed in the nerve/glial antigen-2 (NG2)-positive pericytes and microtubule-associated protein-2 (MAP-2)-positive neurons. Immunoblots revealed reduced Ang-1 expression in the permanent ischemia group and tPA 1-h and 4-h groups compared with that in the sham group (P Conclusions: Delayed tPA treatment after ischemia decreased the pericytic expression of Ang-1, which might play roles in BBB damage after tPA thrombolysis. Ang-1 might be considered a candidate molecule for vasoprotection against HT after tPA thrombolysis. Disclosure: Dr. Kawamira has nothing to disclose. Dr. Igarashi has nothing to disclose. Dr. Kanazawa has nothing to disclose. Dr. Takahashi has nothing to disclose. Dr. Nakada has nothing to disclose. Dr. Nishizawa has nothing to disclose. Dr. Shimohata has nothing to disclose.