An angiogenesis factor, angiopoietin-1 (Ang1), is known to participate in the survival of endothelial cells, vascular remodeling, and vascular stability. In addition, Ang1 has been reported to reduces postischemic vascular hyperpermeability. From the above findings, we hypothesized that Ang1 could attenuate hemorrhagic transformation and cerebral edema after tissue plasminogen activator (tPA) treatment by stabilizing blood vessels and inhibiting hyperpermeability. Sprague-Dawley rats subjected to thromboembolic focal cerebral ischemia were assigned to a permanent ischemia group and groups treated with tPA at 1 h or 4 h after ischemia. The cartilage oligomeric protein (COMP)-Ang1 protein or control protein (COMP protein) was administered immediately before tPA administration in the tPA 4 h group, because recombinant Ang1 protein is poorly soluble. At 24 h after ischemia, we evaluated the effects of the protein on the amount of cerebral hemorrhage, the cerebral edema volume, cerebral infarct volume, and the prognosis with a 6-point neurological score. Ang1 expression was observed in pericytes, astrocytes, and neuronal cells, in the healthy brain tissue of the sham group rats. It was decreased in the BBB when tPA treatment was performed after the therapeutic time window. Administering recombinant COMP-Ang1 to supplement this decrease could suppress hemorrhagic transformation as measured by hemoglobin content in a whole cerebral homogenate and cerebral edema due to BBB damage (Figure A, B). No significant differences were observed between groups for cerebral infarct volume and the neurological scale score (Figure C, D). In conclusion, Ang1 may be considered a promising target molecule for vasoprotective therapies in order to control the hemorrhagic transformation and cerebral edema that accompany tPA treatment.
A Combined Treatment with Tacrolimus (FK506) and Recombinant Tissue Plasminogen Activator for Thrombotic Focal Cerebral Ischemia in Rats: Increased Neuroprotective Efficacy and Extended Therapeutic Time Window
