Angiogenesis plays a central role in many disease processes, and it is expected that modulation of angiogenesis will provide therapeutic benefit. Our proposed study of the mechanisms of cerebral angiogenesis has potential ramifications for patients with cerebral vascular malformations, stroke, and viral infections of the brain. Little is known of how blood vessels develop in response to anglogenic stimuli in the adult brain. We will define the mechanisms of blood vessel formation in the brain and determine whether angiogenesis in the brain differs from that in other tissues. We will use a model that we have developed for cerebral inoculation of adenoviral vector encoding for vascular permeability factor/ vascular endothelial growth factor (VPF/VEGF) in athymic mice. Using techniques of detailed histology and morphometrics, in situ hybridization, cell proliferation and apoptosis studies, and 3-dimensional microscopy, we will examine the detailed mechanisms of how blood vessels develop in the brain. From these studies we will learn what vessels give rise to the new vessels, how they divide into smaller vessels, and the steps and processes involved in the maturation of these newly formed vessels. We will answer the question of whether the vessels formed in the brain by adenoVPF/VEGF differ from normal cerebral blood vessels. The blood brain barrier is unique to cerebral vasculature. Using radio-labeled and fluorescent tracers in addition to electron microscopy, we will examine the effects of VPF/VEGF on normal brain blood vessels and study the mechanistic pathways by which permeability occurs across the blood brain barrier. We will examine the integrity of the blood brain barrier in newly formed vessels throughout the stages of angiogenesis. To test the hypothesis that VPF/VEGF induced formation of cerebral vascular malformations is augmented by ischemia, we will develop a model of chronic cerebral ischemia. We will use this model to determine how mechanisms of angiogenesis are altered in the presence of ischemia.
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