Little is known about the role of Angiogenesis--the sprouting of new capillaries from existing blood vessels--in the natural history of cerebral ischemia, and its therapeutic potential in stroke is largely unexplored. The broad, long-term objective of this project is to identify mechanisms of angiogenesis in cerebral ischemia that can be adapted for therapeutic purposes. The hypotheses to be tested are: (A) Hypoxia can induce the expression and release of vascular endothelial growth factor (VEGF) in cells of the CNS; (B) Hypoxia and VEGF can stimulate the proliferation of cerebral capillary endothelial cells; (C) Ischemia and VEGF can induce angiogenesis in brain; and (D) Cerebral angiogenesis induced by ischemia or by VEGF can improve histological outcome following ischemic stroke.
The specific aims are: 1. Determine the mechanisms through which hypoxia induces the expression of VEGF in neural and astroglial cells, using primary cultures from rat cerebral cortex to evaluate the relative involvement of neurons and astroglia, the role of hypoxia, hypoglycemia and glutamate, the involvement of heme proteins and hypoxia-inducible factor 1, and the level (transcriptional, post-transcriptional, or both) at which the induction of VEGF expression occurs. 2. Investigate how hypoxia stimulates VEGF receptor-mediated angiogenesis in primary cultures of endothelial cells from rat brain microvessels, by examining the effect of hypoxia, hypoglycemia, and hypoxia-conditioned medium on VEGF receptor expression, VEGF receptor-mediated signal transduction (autophosphorylation and calcium mobilization), and VEGF receptor-mediated endothelial cell proliferation. 3. Establish how cerebral ischemia induces VEGF expression, VEGF receptor expression, and angiogenesis, using the suture model of temporary middle cerebral artery occlusion in the rat. 4. Evaluate whether angiogenesis induced by prior focal ischemia or by administration of VEGF can decrease the size of cerebral infarcts in the same model.
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