Granulocyte Colony-Stimulating Factor Attenuates Delayed tPA-Induced Hemorrhagic Transformation in Ischemic Stroke Rats by Enhancing Angiogenesis and Vasculogenesis. Issue 2 (February 2015)

• Record Type: Journal Article
• Authors: dela Peña, Ike C; Yoo, Arum; Tajiri, Naoki; Acosta, Sandra A; Ji, Xunming; Kaneko, Yuji; Borlongan, Cesar V
• Is Part Of: Journal of cerebral blood flow & metabolism. Volume 35:Issue 2(2015)
• Page Start: 338
• Page End: 346
• Publication Date: 2015-02
• Subjects: angiogenesis -- EPCs -- G-CSF -- hemorrhagic transformation -- tPA -- vasculogenesis; Cerebral circulation -- Periodicals; Brain -- Metabolism -- Periodicals; Brain -- Blood-vessels -- Periodicals; Cerebrovascular disease -- Periodicals; 612.824
• DOI: 10.1038/jcbfm.2014.208
• Languages: English
• ISSNs: 0271-678X

Abstract

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.