Granulocyte colony-stimulating factor attenuates delayed tPA-induced hemorrhagic transformation in ischemic stroke rats by enhancing angiogenesis and vasculogenesis

被引:63
作者
dela Pena, Ike C. [1 ]
Yoo, Arum [1 ]
Tajiri, Naoki [1 ,2 ]
Acosta, Sandra A. [1 ]
Ji, Xunming [3 ]
Kaneko, Yuji [1 ]
Borlongan, Cesar V. [1 ]
机构
[1] Univ S Florida, Morsani Coll Med, Dept Neurosurg & Brain Repair, Ctr Excellence Aging & Brain Repair, Tampa, FL 33612 USA
[2] Univ S Florida, Morsani Coll Med, Sch Phys Therapy & Rehabil Sci, Tampa, FL 33612 USA
[3] Capital Med Univ, Xuanwu Hosp, Dept Neurosurg, Beijing, Peoples R China
基金
美国国家卫生研究院;
关键词
angiogenesis; EPCs; G-CSF; hemorrhagic transformation; tPA; vasculogenesis; TISSUE-PLASMINOGEN ACTIVATOR; ENDOTHELIAL PROGENITOR CELLS; FUNCTIONAL RECOVERY; GROWTH-FACTOR; G-CSF; NEOVASCULARIZATION; MOBILIZATION; COMBINATION; MECHANISMS; PHASE;
D O I
10.1038/jcbfm.2014.208
中图分类号
R5 [内科学];
学科分类号
1002 ; 100201 ;
摘要
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 mu g/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.
引用
收藏
页码:338 / 346
页数:9
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