Granulocyte Colony-Stimulating Factor Attenuates Delayed tPA-Induced Hemorrhagic Transformation in Ischemic Stroke Rats by Enhancing Angiogenesis and Vasculogenesis

• Published in: Journal of cerebral blood flow and metabolism Vol. 35; no. 2; pp. 338 - 346
• Main Authors: dela Peña, Ike C, Yoo, Arum, Tajiri, Naoki, Acosta, Sandra A, Ji, Xunming, Kaneko, Yuji, Borlongan, Cesar V
• Format: Journal Article
• Language: English
• Published: London, England SAGE Publications 01.02.2015; Sage Publications Ltd; Nature Publishing Group
• Subjects: Animals; Antigens, CD34 - biosynthesis; Brain Ischemia - drug therapy; Brain Ischemia - metabolism; Brain Ischemia - pathology; Cerebral Cortex - metabolism; Cerebral Cortex - pathology; Corpus Striatum - metabolism; Corpus Striatum - pathology; Gene Expression Regulation - drug effects; Intracranial Hemorrhages - chemically induced; Intracranial Hemorrhages - drug therapy; Intracranial Hemorrhages - pathology; Male; Neovascularization, Physiologic - drug effects; Original; Rats; Rats, Sprague-Dawley; Stroke - drug therapy; Stroke - metabolism; Stroke - pathology; Tissue Plasminogen Activator - adverse effects; Tissue Plasminogen Activator - pharmacology; Vascular Endothelial Growth Factor Receptor-2 - biosynthesis; von Willebrand Factor - biosynthesis; vasculogenesis; EPCs; tPA; hemorrhagic transformation; G-CSF; angiogenesis
• ISSN: 0271-678X; 1559-7016; 1559-7016
• DOI: 10.1038/jcbfm.2014.208

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.