Expression of vascular endothelial growth factor by reactive astrocytes and associated neoangiogenesis

Injury to the central nervous system (CNS) invokes a reparative response known as astrogliosis, characterized largely by hypertrophy, proliferation and increased expression of glial fibrillary acidic protein (GFAP), resulting in reactive astrocytosis. Based on our prior observation that peritumoral reactive astrocytes express Vascular Endothelial Growth Factor (VEGF), a highly potent and specific angiogenic growth factor, we have hypothesized that reactive astrocytosis also contributes to the neovascularization associated with astrogliosis. To evaluate this hypothesis we evaluated human surgical/autopsy specimens from a variety of CNS disorders that induce astrogliosis and an experimental CNS needle injury model in wild type and GFAP:Green Fluorescent Protein (GFP) transgenic mice. Using computer image semi-quantitative analysis we evaluated the number of GFAP-positive reactive astrocytes, degree of VEGF expression by these astrocytes, associated Factor VIII-positive microvascular density (MVD) and Ki-67 proliferating endothelial cells. The degree of reactive astrocytosis correlated to levels of VEGF immunoreactivity and MVD in the neuropathological specimens. The mouse-needle-stick brain injury model demonstrated this correlation was temporally and spatially related and maximal after 1 week. These results, involving both human pathology specimens augmented by experimental animal data, supports our hypothesis that the neoangiogenesis associated with reactive astrogliosis is correlated to increased reactive astrocytosis and associated VEGF expression.