Postischemic IGF-1 gene transfer promotes neurovascular regeneration after experimental stroke.
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.
Zhu
Wei
W
Department of Anesthesia and Perioperative Care, Center for Cerebrovascular Research, University of California San Francisco, San Francisco, California, USA.
Fan
Yongfeng
Y
Hao
Qi
Q
Shen
Fanxia
F
Hashimoto
Tomoki
T
Yang
Guo-Yuan
GY
Gasmi
Mehdi
M
Bartus
Raymond T
RT
Young
William L
WL
Chen
Yongmei
Y
D000818:Animals; D002545:Brain Ischemia / Q000378:metabolism / Q000473:pathology / Q000628:therapy; D002560:Cerebrovascular Circulation / Q000502:physiology; D000089662:Doublecortin Protein; D018014:Gene Transfer Techniques; D015316:Genetic Therapy / Q000379:methods*; D005822:Genetic Vectors / Q000235:genetics / Q000378:metabolism; D006801:Humans; D007334:Insulin-Like Growth Factor I / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008833:Microcirculation; D018919:Neovascularization, Physiologic / Q000502:physiology*; D012039:Regional Blood Flow / Q000502:physiology; D014161:Transduction, Genetic
C000714847:Dcx protein, mouse; D000089662:Doublecortin Protein; D007334:Insulin-Like Growth Factor I