Effects of angiopoietin-1 on hemorrhagic transformation and cerebral edema after tissue plasminogen activator treatment for ischemic stroke in rats.
Effects of angiopoietin-1 on hemorrhagic transformation and cerebral edema after tissue plasminogen activator treatment for ischemic stroke in rats.
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DOI：
10.1371/journal.pone.0098639
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发表时间：
2014
期刊：
影响因子：
3.7
通讯作者：
Shimohata T
中科院分区：
文献类型：
--
作者：
Kawamura K;Takahashi T;Kanazawa M;Igarashi H;Nakada T;Nishizawa M;Shimohata T
血管生成因子血管生成素-1(Ang1)与脑缺血后血脑屏障(BBB)的破坏有关。然而，组织纤溶酶原激活物(TPA)治疗后的出血性转化和脑水肿是否与血脑屏障中Ang1表达的减少有关尚不清楚。我们推测，给予Ang1可能通过稳定血管和抑制高通透性来减轻tPA治疗后的出血性转化和脑水肿。SD大鼠制作血栓栓塞性局灶性脑缺血模型，分为永久性缺血组(永久性大脑中动脉闭塞，PMCAO)和缺血后1h或4h给予tPA治疗组。内源性Ang1在周细胞、星形胶质细胞和神经细胞中均有表达。Western印迹分析显示，tPA-1h、tPA-4h和PMCAO组缺血侧大脑皮质血管紧张素转换酶1的表达水平低于对照组(P = 分别为0.014、0.003和0.014)。TPA-4h组和PMCAO组的血管密度均低于对照组(p = 分别为0.002和0.001)和tPA-1h组(p = 分别为0.047和0.005)。这些结果表明，在治疗时间窗(1h)内给予tPA可维持血管内皮细胞Ang1阳性血管密度，而在治疗时间窗(4h)后给予tPA可使其血管密度降低。与单独使用软骨低聚蛋白(CoMP)相比，使用与软骨低聚蛋白(CoMP)融合的Ang1来补充这一下降具有抑制出血性转化(以全脑匀浆中的血红蛋白含量衡量)的潜力(p = 0.007)和由血脑屏障损伤引起的脑水肿(p = 0.038)。综上所述，Ang1可能成为控制tPA治疗后出血转化和脑水肿的血管保护治疗的一个有前途的靶分子。
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.
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作者：
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