Proliferation and differentiation of the cerebral blood vessels

胚胎发育过程中的脑血管生成是由发育中的脑组织中的局部缺氧引起的，尤其是血管内皮生长因子(VEGE)在缺氧时的上调起着至关重要的作用。通过对低氧诱导血管内皮生长因子基因转录激活的分子机制的研究，我们发现发育中的脑血管生成受脑细胞中转录因子低氧诱导因子I和AP1的产生的调节。在血管生成过程中，脑血管分化为血脑屏障(BBB)形成血管，我们的研究表明，发育中的脑细胞能够产生诱导内皮细胞中血脑屏障特性的因子。此外，我们还发现，发育中的脑细胞在整个发育过程中都表达VEGF122和VEGF166，而VEGF146和VEGF190则在脑血管分化的低峰期开始表达。考虑到VEGF不仅是控制血管生成的因素，也是控制血管通透性的因素，这种VEGF亚型表达模式的变化表明，VEGF可能也参与了EBV的诱导。对脑、肺、肾组织中血管内皮生长因子表达的比较研究表明，VEGF146亚型在蜜蜂诱导期和诱蜂后脑组织中的表达具有特异性。原位杂交研究表明，在蜜蜂诱导期表达VEGF的细胞是发育中的脑细胞。这些结果提示，脑细胞发育所产生的VEGFI46可能与其诱发衰退特性的能力有关。为了探讨VEGFI46在ebb诱导中的功能作用，我们克隆了VEGFL22、146、166、190等不同亚型的基因，并建立了表达各亚型的细胞。他们现在正在接受调查。

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.