Abstract
The blood-brain barrier (BBB) is essential for maintaining brain homeostasis and low permeability. BBB maintenance is important in the central nervous system (CNS) because disruption of the BBB may contribute to many brain disorders, including Alzheimer disease and ischemic stroke. The molecular mechanisms of BBB development remain ill-defined, however. Here we report that src-suppressed C-kinase substrate (SSeCKS) decreases the expression of vascular endothelial growth factor (VEGF) through AP-1 reduction and stimulates expression of angiopoietin-1 (Ang-1), an antipermeability factor in astrocytes. Conditioned media from SSeCKS-overexpressing astrocytes (SSeCKS-CM) blocked angiogenesis in vivo and in vitro. Moreover, SSeCKS-CM increased tight junction proteins in endothelial cells, consequently decreasing [3H]sucrose permeability. Furthermore, immunoreactivity to SSeCKS gradually increased during the BBB maturation period, and SSeCKS-expressing astrocytes closely interacted with zonula occludens (ZO)-1-expressing blood vessels in vivo. Collectively, our results suggest that SSeCKS regulates BBB differentiation by modulating both brain angiogenesis and tight junction formation.
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Acknowledgements
We thank K. Kim and J.-H. Park (School of Biological Sciences, Seoul National University, Korea) and M. Kim (College of Medicine, Seoul National University, Korea) for helpful discussions about brain histology. Financial support was from the Vascular System Research Center grant from the Korea Science and Engineering Foundation and the National Research Laboratory Fund (2002-N-NL-01-C-015), and Ministry of Science and Technology, Korea (to K.-W. K).
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Lee, SW., Kim, W., Choi, Y. et al. SSeCKS regulates angiogenesis and tight junction formation in blood-brain barrier. Nat Med 9, 900–906 (2003). https://doi.org/10.1038/nm889
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DOI: https://doi.org/10.1038/nm889
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