Proliferation and differentiation of the cerebral blood vessels

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Cerebral angiogenesis during embryogenesis is triggered by focal hypoxia in the developing brain tissue, and especially, the up-regulation of vascular endothelial growth factor (VEGE) in response to hypoxia is crucial. Through investigation into the molecular mechanisms of hypoxia-induced transcriptional activation of the VEGF gene, we showed that cerebral angiogenesis in the developing brain is regulated by production of the transcriptional factors, hypoxia-inducible factor I and AP1, in brain cells. As concerns the differentiation of cerebral vessels into the blood-brain barrier (BBB)-forming vessels which follows the angiogenesis, our studies using the xenograft transplantation system between quail and chick embryos showed that developing brain cells produce factors capable of inducing the BBB properties in endothelial cells. Furthermore, we found the fact that developing brain cells express the VEGF isoforms VEGF122 and VEGF166 throughout the development, whereas the isoforms VEGF146 and VEGF190 start to be expressed around the period of EBB differentiation of cerebral vessels. Considering that VEGF is the factor controlling not only angiogenesis but vascular permeability, this alteration of VEGF isoform expression pattern suggests the possible contribution of VEGF also to the EBB induction. Comparative study on the VEGF expression between brain, lung and kidney showed the expression of isoform VEGF 146 to be specific for the brain tissue at and after the stage of BEE induction. In situ hybridization study revealed that cells expressing VEGF during the period of BEE induction are developing brain cells. These results suggest the possible relation between the production off VEGFI46 by developing brain cells and their capability of inducing the EBB properties. To discuss the functional role of VEGFI46 in the EBB induction, we have cloned VEGF isoforms (VEGFL22, 146, 166,190) cDNAs and established the cells expressing each isoform. They are now under investigation.