Postischemic IGF-1 gene transfer promotes neurovascular regeneration after experimental stroke

• Published in: Journal of cerebral blood flow and metabolism Vol. 29; no. 9; pp. 1528 - 1537
• Main Authors: Zhu, Wei, Fan, Yongfeng, Hao, Qi, Shen, Fanxia, Hashimoto, Tomoki, Yang, Guo-Yuan, Gasmi, Mehdi, Bartus, Raymond T, Young, William L, Chen, Yongmei
• Format: Journal Article
• Language: English
• Published: London, England SAGE Publications 01.09.2009; Nature Publishing Group; Sage Publications Ltd
• Subjects: Adeno-associated virus; Animals; Biological and medical sciences; Brain Ischemia - metabolism; Brain Ischemia - pathology; Brain Ischemia - therapy; Cerebrovascular Circulation - physiology; Gene Transfer Techniques; Genetic Therapy - methods; Genetic Vectors - genetics; Genetic Vectors - metabolism; Headache. Facial pains. Syncopes. Epilepsia. Intracranial hypertension. Brain oedema. Cerebral palsy; Humans; Insulin-Like Growth Factor I - genetics; Insulin-Like Growth Factor I - metabolism; Medical sciences; Mice; Microcirculation; Neovascularization, Physiologic - physiology; Nervous system (semeiology, syndromes); Neurology; Regional Blood Flow - physiology; Transduction, Genetic; Vascular diseases and vascular malformations of the nervous system; neurovascular; IGF-1; regeneration; stroke; angiogenesis; Vascular disease; Angiogenesis; Regeneration; Stroke; Nervous system diseases; Ischemia; Central nervous system disease; Cardiovascular disease; Cerebrovascular disease; Cerebral disorder
• ISSN: 0271-678X; 1559-7016
• DOI: 10.1038/jcbfm.2009.75

Promoting neural regeneration after cerebral infarction has emerged as a potential approach for the treatment of stroke. Insulin-like growth factor 1 (IGF-1) possesses both neurotrophic and angiogenic properties. The aim of this study was to determine whether postischemic gene transfer of IGF-1 enhances neurovascular regeneration in a mouse model of permanent focal cerebral ischemia. Long-term cerebral IGF-1 overexpression was achieved with adeno-associated viral vector (AAV) by stereotaxic injection at 24 h after a stroke. Adeno-associated viral vector-green fluorescent protein (GFP) or saline was injected as a control. The success of postischemic gene transduction was confirmed by a strong GFP signal and by increased IGF-1 protein expression in the peri-infarct region. Postischemic gene transfer of IGF-1 significantly enhanced vascular density at 8 weeks after a stroke in the peri-infarct and injection needle tract area compared with AAV-GFP or saline treatment, as shown by immunohistochemical staining with the vascular marker lectin. Furthermore, increased vascular density was associated with improved local vascular perfusion. Immunohistochemical staining with the neuronal progenitor marker, DCX (doublecortin), and the cell proliferation marker, BrdU (5-bromo-2-deoxyuridine-5-monophosphate), indicated that AAV-IGF-1 treatment potently increased neurogenesis compared with AAV-GFP injection. These data show that postischemic treatment of IGF-1 effectively promoted neural and vascular regeneration in the chronic stage of cerebral infarction.