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

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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.