Granulocyte colony-stimulating factor attenuates delayed tPA-induced hemorrhagic transformation in ischemic stroke rats by enhancing angiogenesis and vasculogenesis.
Granulocyte colony-stimulating factor attenuates delayed tPA-induced hemorrhagic transformation in ischemic stroke rats by enhancing angiogenesis and vasculogenesis.
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通过增强血管生成和血管生成，粒细胞刺激性刺激因子减弱了缺血性卒中大鼠TPA诱导的出血转化。
DOI：
10.1038/jcbfm.2014.208
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发表时间：
2015-02
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超过治疗时间窗(卒中后4.5小时)使用组织纤溶酶原激活剂(TPA)治疗可能会产生出血性转化(HT)。可以延长tPA狭窄时间窗口的策略将使相当数量的中风患者受益。雄性SD大鼠大脑中动脉闭塞后6h给予tPA(10 mg/kg)或tPA+粒细胞集落刺激因子(GCSF300 μg/kg)。治疗24小时后，G-CSF+tPA治疗的中风大鼠神经功能改善25%，出血减少38.9%，Western blots显示缺血皮质和纹状体Ang-2的表达分别增加1.9和1.2倍，同侧皮质磷酸化内皮型一氧化氮合酶的表达比tPA治疗的大鼠增加3倍。免疫组织化学还显示，与tPA治疗组相比，G-CSF+tPA治疗组大鼠缺血皮质和纹状体von-Willebrand表达分别增加2倍和2.8倍，CD34+表达分别增加3.2倍和2.2倍，VEGFR-2表达分别上调4倍和13倍。综上所述，这些发现表明，G-CSF可能通过促进血管生成和血管生成来减轻tPA诱导的延迟性高血压。使用G-CSF保护血管系统可能会改善tPA的临床结果，即使超出了目前所指出的缺血性卒中的治疗窗口。
Treatment with tissue plasminogen activator (tPA) beyond the therapeutic time window (>4.5 hours post stroke) may produce hemorrhagic transformation (HT). Strategies that could extend the narrow time window of tPA will benefit a significant number of stroke patients. Male Sprague–Dawley rats underwent middle cerebral artery occlusion (MCAo) and given vehicle, tPA (10 mg/kg), or tPA and granulocyte colony-stimulating factor (G-CSF, 300 μg/kg), at 6 hours after MCAo. Twenty-four hours post treatment, G-CSF+tPA-treated stroke rats displayed 25% improvement in neurological functions and 38.9% reduction of hemorrhage, with Western blots showing 1.9- and 1.2-fold increments in Ang-2 expression in the ischemic cortex and striatum, respectively, and 3-fold increase in phosphorylated endothelial nitric oxide synthase expression in the ipsilateral cortex relative to tPA-treated rats. Immunohistochemistry also showed 2- and 2.8-fold increase in von-Willebrand expression, 3.2- and 2.2-fold increased CD34+ expression, and 4- and 13-fold upregulation of VEGFR-2 expression in the ischemic cortex and striatum, respectively, in G-CSF+tPA-treated stroke rats relative to tPA-treated subjects. Altogether, these findings indicate that G-CSF attenuated delayed tPA-induced HT likely via the enhancement of angiogenesis and vasculogenesis. The use of G-CSF to protect the vasculature may improve the clinical outcome of tPA even outside the currently indicated therapeutic window for ischemic stroke.
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