Nature Medicine9, 900 - 906 (2003)
Published online: 15 June 2003; | doi:10.1038/nm889
SSeCKS regulates angiogenesis and tight junction formation in blood-brain barrier
Sae-Won Lee1, 2, 4, Woo Jean Kim1, 2, 4, Yoon Kyung Choi1, Hyun Seok Song1, 2, Myung Jin Son1, 2, Irwin H. Gelman3, Yung-Jin Kim2
& Kyu-Won Kim1
1
Research Institute of Pharmaceutical Sciences, College of Pharmacy, Seoul National University, Seoul 151-742, Korea.
2
Department of Molecular Biology, Pusan National University, Busan 609-735, Korea.
3
Department of Medicine and Ruttenberg Cancer Center, Division of Infectious Diseases, Mount Sinai School of Medicine, New York, New York 10029-6574, USA.
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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