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SSeCKS regulates angiogenesis and tight junction formation in blood-brain barrier

Nature Medicine volume 9, pages 900–906 (2003)Cite this article

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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Figure 1: Regulation of SSeCKS expression by oxygen tension.
Figure 2: Antiangiogenic activity of SSeCKS in vivo and in vitro.
Figure 3: SSeCKS overexpression decreases VEGF expression and AP-1 transcriptional activity.
Figure 4: Regulation of vascular permeability and expression of BBB marker genes by SSeCKS-transfected astrocytes.
Figure 5: Immunohistochemical staining of SSeCKS, VEGF and ZO-1 in developing mouse brain.
Figure 6: Double immunostaining of SSeCKS, GFAP and ZO-1 in the adult mouse brain.

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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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  1. Sae-Won Lee and Woo Jean Kim: These authors contributed equally to this work.

Authors and Affiliations

  1. Research Institute of Pharmaceutical Sciences, College of Pharmacy, Seoul National University, Seoul, 151-742, Korea

    Sae-Won Lee, Woo Jean Kim, Yoon Kyung Choi, Hyun Seok Song, Myung Jin Son & Kyu-Won Kim

  2. Department of Molecular Biology, Pusan National University, Busan, 609-735, Korea

    Sae-Won Lee, Woo Jean Kim, Hyun Seok Song, Myung Jin Son & Yung-Jin Kim

  3. Department of Medicine and Ruttenberg Cancer Center, Division of Infectious Diseases, Mount Sinai School of Medicine, New York, 10029-6574, New York, USA

    Irwin H. Gelman

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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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