CELLULAR AND MOLECULAR BASIS OF ANGIOGENESIS IN DEVELOPING BRAIN

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In the developing brain, the cerebral microvessels exhibit plasticity. In response to chronic sublethal hypoxia, preliminary studies demonstrate significant cortical angiogenesis and permeability changes. Although this response is believed to improve metabolic supply during critical periods of corticogenesis, the mechanisms underlying it are largely unknown as are the long-term consequences of this microvascular response. The three-dimensional beagle brain microvascular endothelial cells (BBMEC)/neonatal rat astrocyte coculture provides a good model for the study of the developing cerebral microvasculature. This system demonstrates the development of the characteristics of the blood-brain barrier in vitro and undergoes active angiogenesis in response to chronic sublethal hypoxia stress. We hypothesize that this system will provide a model for the study of growth factor mediated glial endothelial signaling which occurs secondary to chronic sublethal hypoxia insult. Previous experience suggests that vascular endothelial growth factor (VEGF), transforming growth factor-beta (TGF-beta) and fibroblast growth factor (FGF) are critical to this response, and our studies will target these three growth factors. We will also test the hypothesis that those growth factors found to be critical for the hypoxic induction of angiogenesis in vitro will mediate not only the hypoxic induction of angiogenesis but also the changes in microvascular permeability found in vivo. In addition to studies of animals reared in chronic sublethal hypoxia, we will implant fibroblasts stably transfected with an expressing these growth factors into the cortex of neonatal rats to stimulate our model of chronic sublethal hypoxia. Finally, using the neonatal rat model, we will test the hypothesis that those genes identified as being differentially regulated in both development and hypoxia in vitro will also play a role in the hypoxic induction of angiogenesis in vivo.