Abstract
An angiogenesis factor, angiopoietin-1 (Ang1), is associated with the blood-brain barrier (BBB) disruption after focal cerebral ischemia. However, whether hemorrhagic transformation and cerebral edema after tissue plasminogen activator (tPA) treatment are related to the decrease in Ang1 expression in the BBB remains unknown. We hypothesized that administering Ang1 might attenuate hemorrhagic transformation and cerebral edema after 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 (permanent middle cerebral artery occlusion; PMCAO) and groups treated with tPA at 1 h or 4 h after ischemia. Endogenous Ang1 expression was observed in pericytes, astrocytes, and neuronal cells. Western blot analyses revealed that Ang1 expression levels on the ischemic side of the cerebral cortex were decreased in the tPA-1h, tPA-4h, and PMCAO groups as compared to those in the control group (P = 0.014, 0.003, and 0.014, respectively). Ang1-positive vessel densities in the tPA-4h and PMCAO groups were less than that in the control group (p = 0.002 and <0.001, respectively) as well as that in the tPA-1h group (p = 0.047 and 0.005, respectively). These results suggest that Ang1-positive vessel density was maintained when tPA was administered within the therapeutic time window (1 h), while it was decreased when tPA treatment was given after the therapeutic time window (4 h). Administering Ang1 fused with cartilage oligomeric protein (COMP) to supplement this decrease has the potential to suppress hemorrhagic transformation as measured by hemoglobin content in a whole cerebral homogenate (p = 0.007) and cerebral edema due to BBB damage (p = 0.038), as compared to administering COMP protein alone. In conclusion, Ang1 might be a promising target molecule for developing vasoprotective therapies for controlling hemorrhagic transformation and cerebral edema after tPA treatment.
Highlights
Thrombolytic treatment with tissue plasminogen activators has been approved by the U.S Food and Drug Administration as a standard treatment for cerebral infarction, and its therapeutic time window has recently been expanded to 4.5 h after onset [1]
We previously demonstrated that tissue plasminogen activators (tPA) treatment after the therapeutic time window promoted expression of an endothelial cell–specific growth factor, vascular endothelial cell growth factor (VEGF), in blood brain barrier (BBB), MMP-9 activation, degradation of BBB components, and hemorrhagic transformation using a rat model of thromboembolic focal cerebral ischemia [3],[4]
In 3D images of RECA1 and endogenous Ang1, endogenous Ang1 expression was not observed in endothelial cells, but the expression of Ang1 is consistent with the localization pattern of pericytes (Figure 1Ba)
Summary
Thrombolytic treatment with tissue plasminogen activators (tPA) has been approved by the U.S Food and Drug Administration as a standard treatment for cerebral infarction, and its therapeutic time window has recently been expanded to 4.5 h after onset [1]. While tPA treatment can be expected to greatly improve functional prognosis, administering it after its therapeutic time window can cause hemorrhagic transformation, exacerbate neurological symptoms, and even put the patient’s life in danger [2]. We previously demonstrated that tPA treatment after the therapeutic time window promoted expression of an endothelial cell–specific growth factor, vascular endothelial cell growth factor (VEGF), in BBB, MMP-9 activation, degradation of BBB components, and hemorrhagic transformation using a rat model of thromboembolic focal cerebral ischemia [3],[4]. Compared with tPA and control antibody, combination treatment with tPA and the anti-VEGF neutralizing antibody significantly attenuated VEGF expression in BBB, MMP-9 activation, degradation of BBB components, and hemorrhagic transformation, and it improved motor outcome and mortality [3]. Inhibition of VEGF signaling pathway may be a promising therapeutic strategy for attenuating hemorrhagic transformation after tPA treatment
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