Molecular mechanisms of the blood-brain barrier induction in cerebral blood vessels

中枢神经微环境是由b90血脑屏障（BBB）维持的。血脑屏障是由神经组织特异性血管内皮细胞形成的。利用鹌鹑和鸡胚异种移植诱导血脑屏障的体内模型，我们发现在鹌鹑中VEGF亚型（VEGF_< 122,146,166,190 >）中，VEGF_<146>的表达在血脑屏障分化启动后仅在胚胎脑组织中上调。这一发现提示VEGF不仅参与胚胎脑血管生成过程，还通过其异构体表达模式的改变参与血脑屏障诱导过程。视网膜血管中有与血脑屏障相对应的血视网膜屏障（BRB）， BRB的破坏在糖尿病视网膜病变中被注意到。然后，为了探讨VEGF-VEGF受体系统与BRB功能的关系，我们分析了VEGF亚型（在人体内，VEGF_<121、145、165、189、206>）及其受体（VEGF- r1、VEGF- r2、neuropilin-1）在糖尿病视网膜病变患者眼内病变中的表达情况。将VEGF异构体和VEGF受体的表达模式与病变活动性进行比较，发现病变高活性与VEGF_<165>、VEGF- r2和neuropilin-1的表达密切相关。考虑到neuropilin-1是VEGF_<165>特异性受体，通过VEGF-R2增强VEGF_<165>的胞质内信号传导，我们的数据提示VEGF_<165>在糖尿病视网膜病变视网膜病变的形成中起重要作用。以上从禽类系统和人类糖尿病视网膜病变中获得的结果使我们认为VEGF通过改变同型异构体表达模式参与了血脑屏障诱导过程。

Microenvironment of central nerve system is maintained by the b90 lood-brain barrier (BBB). The BBB is formed by the neural tissue-specific vascular endothelial cells. Using an in vivo model of BBB induction which is based on the xenograft transplantation between quail and chick embryos, we showed that, among the quail VEGF isoforms (in quail, VEGF_<122, 146, 166, 190>), VEGF_<146> expression is up-regulated exclusively in the embryonic brain tissues after the BBB differentiation initiated. This finding suggests the involvement of VEGF not only in the process of embryonic brain angiogenesis but also in that of BBB induction through the changes in its isoform expression pattern. Blood vessels in retina have a counterpart of BBB called the blood-retinal barrier (BRB), and the breakdown of BRB is noted in diabetic retinopathy. Then, in order to discuss the relationship between VEGF-VEGF receptors system and BRB function, we analysed the expression of VEGF isoforms (in human, VEGF_<121, 145, 165, 189, 206>) and its receptors (VEGF-R1, VEGF-R2, neuropilin-1) in intraocular lesions of the patients with diabetic retinopathy. When the expression patterns of VEGF isoforms and VEGF receptors are compared with the activity of the lesions, close correlation was observed between the high activity of lesions and the expression of VEGF_<165>, VEGF-R2 and neuropilin-1. Considering that neuropilin-1 is a VEGF_<165>-specific receptor to enhance the intracytoplasmic signalling from VEGF_<165> via VEGF-R2, our data suggested that VEGF_<165> plays an important role in the formation of retinal lesions in diabetic retinopathy. The above results obtained from the avian system as well as the human diabetic retinopathy lead us to the idea that VEGF is involved in the process of BBB induction through the changes in the isoform expression pattern.