VEGF is an angiogenesis (1
) and vascular permeability (2
) factor that undergoes transcriptional and posttranscriptional induction by hypoxia; it couples hypoxia to angiogenesis in diverse tissues (3
), including the brain (4
). VEGF may have an important role in the vascular response to cerebral ischemia, because ischemia stimulates VEGF expression in the brain (5
) and VEGF promotes the formation of new cerebral blood vessels (10
). Topical administration of VEGF to the surface of the brain reduces infarct size (12
), intravenous VEGF improves neurological outcome (13
), and intraventricular administration of an anti-VEGF Ab increases infarct size (14
) after focal cerebral ischemia. These findings are consistent with a protective effect of VEGF, although it is unclear if angiogenesis is responsible. Moreover, cerebral vessels formed in response to VEGF are abnormally leaky (9
), which could exacerbate cerebral edema and worsen the outcome from ischemia.
VEGF also exerts direct effects on neurons. For example, VEGF stimulates axonal outgrowth and improves the survival of cultured superior cervical and dorsal-route ganglion neurons (15
) and enhances the survival of mesencephalic neurons in organotypic explant cultures (17
). VEGF protects HN33 (mouse hippocampal neuron × neuroblastoma) cells from death induced by serum withdrawal (18
) and reduces hypoxic death of both HN33 cells and cultured cerebral cortical neurons (19
). Additional evidence for direct neuronal protection by VEGF is that VEGF inhibits the death of cultured hippocampal neurons from glutamate (21
) and N
) toxicity and that deletion of the hypoxia-response element from the VEGF promoter causes motor-neuron degeneration in mice (23
). Because neuroprotective effects of other growth factors are associated with improved outcome from stroke, this could be true for VEGF as well.
Finally, VEGF has been implicated as a factor that promotes neurogenesis in the adult brain. One possibility is that this occurs through the establishment of a vascular niche that favors the proliferation and differentiation of neuronal precursors (24
), perhaps by the release of brain-derived neurotrophic factor from endothelial cells (25
). Alternatively, VEGF may exercise a direct mitogenic effect on neuronal precursors (26
). Thus, VEGF expression in the ischemic brain could contribute to ischemia-induced neurogenesis (27
) and modify outcome in that way as well.
We investigated the relationships among three effects of VEGF that might be important determinants of outcome from cerebral ischemia — neuroprotection, neurogenesis, and angiogenesis — in a rat model of transient focal ischemia induced by middle cerebral artery occlusion (MCAO). Because previous evidence indicated that VEGF improves neurological recovery when given 48 hours, but not 1 hour, after ischemia (13
), we delayed VEGF administration (1–3 days after ischemia) in these studies as well. Our results suggest that VEGF exerts multiple, independent effects on the ischemic brain that may modify both short-term and long-term outcome after stroke.