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.

Project Start
2000-05-01
Project End
2001-04-30
Budget Start
1997-10-01
Budget End
1998-09-30
Support Year
4
Fiscal Year
2000
Total Cost
$293,069
Indirect Cost
Name
Yale University
Department
Type
DUNS #
082359691
City
New Haven
State
CT
Country
United States
Zip Code
06520
Komitova, Mila; Xenos, Dionysios; Salmaso, Natalina et al. (2013) Hypoxia-induced developmental delays of inhibitory interneurons are reversed by environmental enrichment in the postnatal mouse forebrain. J Neurosci 33:13375-87
Silbereis, John; Heintz, Tristan; Taylor, Mary Morgan et al. (2010) Astroglial cells in the external granular layer are precursors of cerebellar granule neurons in neonates. Mol Cell Neurosci 44:362-73
Fagel, Devon M; Ganat, Yosif; Cheng, Elise et al. (2009) Fgfr1 is required for cortical regeneration and repair after perinatal hypoxia. J Neurosci 29:1202-11
Silbereis, John; Cheng, Elise; Ganat, Yosif M et al. (2009) Precursors with glial fibrillary acidic protein promoter activity transiently generate GABA interneurons in the postnatal cerebellum. Stem Cells 27:1152-63
Madri, J A (2009) Modeling the neurovascular niche: implications for recovery from CNS injury. J Physiol Pharmacol 60 Suppl 4:95-104
Chahboune, Halima; Ment, Laura R; Stewart, William B et al. (2009) Hypoxic injury during neonatal development in murine brain: correlation between in vivo DTI findings and behavioral assessment. Cereb Cortex 19:2891-901
Rauch, Millicent Ford; Michaud, Michael; Xu, Hao et al. (2008) Co-culture of primary neural progenitor and endothelial cells in a macroporous gel promotes stable vascular networks in vivo. J Biomater Sci Polym Ed 19:1469-85
Constable, R Todd; Ment, Laura R; Vohr, Betty R et al. (2008) Prematurely born children demonstrate white matter microstructural differences at 12 years of age, relative to term control subjects: an investigation of group and gender effects. Pediatrics 121:306-16
Li, Qi; Michaud, Michael; Stewart, William et al. (2008) Modeling the neurovascular niche: murine strain differences mimic the range of responses to chronic hypoxia in the premature newborn. J Neurosci Res 86:1227-42
Glantz, Susan B; Cianci, Carol D; Iyer, Rathna et al. (2007) Sequential degradation of alphaII and betaII spectrin by calpain in glutamate or maitotoxin-stimulated cells. Biochemistry 46:502-13

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