DICKIE, R; Harvard University: Normal and aberrant angiogenesis in the brain: morphological consequences of genotypic differences in neural stem cells and the role of hypoxia

There are common molecular and morphological themes in the development of normal and neoplastic glia; here we focus on those associated with the vasculature. During embryonic development, vascular sprouts penetrate into the brain attracted by high levels of vascular endothelial growth factor (VEGF) in the ventricles. Postnatally, angiogenesis declines and growth of the brain is accommodated by elongation of pre-existing vessels. Hypoxia is another stimulator of angiogenesis, and it has been hypothesized that hypoxia in developing embryonic tissues induces vascular development. Here we investigate the role of epidermal growth factor receptor (EGFR), a potential modulator of VEGF, in the induction of angiogenesis using mutant neural stem cells/glial cells, and assess the role of hypoxia on vascular morphology in this system. While much is known about the cellular and biochemical activities of these genes, little is known about their biological consequences. We investigated the architecture and density of normal brain vasculature and mutant glia-associated vasculature using morphometric and stereological analysis of cardiac perfused, cleared whole-mount brains imaged by confocal microscopy. Comparing double and triple mutants, differences were found in vascular density, ability to perfuse tissue, and response to angiogenesis inhibitors.