Insulin Growth Factor-1 Gene Transfer Enhances Neurovascular Remodeling and Improves Long-Term Stroke Outcome in Mice

Abstract

Insulin-like growth factor I (IGF-1) is a pleiotropic growth factor that has been demonstrated to protect against acute ischemic brain injury. Whether IGF-1 improves long-term functional outcome after ischemic stroke is not known. The aim of this study is to examine whether IGF-1 overexpression through adeno-associated virus (AAV) -mediated gene transfer enhances neurovascular remodeling and improves functional outcome in a mouse model of focal cerebral ischemia. Long-term cerebral IGF-1 overexpression was achieved with the AAV transduction system through stereotaxic injection. Control mice were injected with AAV-green fluorescent protein or saline. Three weeks after gene transfer, the mice underwent permanent distal middle cerebral artery occlusion. Histological and behavioral analyses were performed at day 21 after middle cerebral artery occlusion. IGF-1 gene transfer compared with control treatment significantly improved motor performance assessed by sensorimotor tests. The functional recovery was accompanied by reduced volume of cerebral infarction. Immunohistochemical analysis with endothelial cell marker CD31 revealed that IGF-1 gene transfer potently increased neovessel formation in the periinfarct and injection needle tract area compared with AAV-green fluorescent protein transduction. Increased vascular density was associated with increased local vascular perfusion. Additionally, AAV-IGF-1 treatment enhanced neurogenesis in the subventricular zone compared with AAV-green fluorescent protein treatment. These data demonstrate that IGF-1 overexpression promoted long-lasting functional recovery after cerebral infarction. The improved functional performance was paralleled by enhanced neovascularization and neurogenesis.