Lee Sae-Won, Kim Woo Jean, Choi Yoon Kyung, Song Hyun Seok, Son Myung Jin, Gelman Irwin H, Kim Yung-Jin, Kim Kyu-Won
Research Institute of Pharmaceutical Sciences, College of Pharmacy, Seoul National University, Seoul 151-742, Korea.
Nat Med. 2003 Jul;9(7):900-6. doi: 10.1038/nm889.
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.
血脑屏障（BBB）对于维持脑内稳态和低通透性至关重要。血脑屏障的维持在中枢神经系统（CNS）中很重要，因为血脑屏障的破坏可能导致许多脑部疾病，包括阿尔茨海默病和缺血性中风。然而，血脑屏障发育的分子机制仍不清楚。在此，我们报告src抑制的C激酶底物（SSeCKS）通过降低AP-1的表达来减少血管内皮生长因子（VEGF）的表达，并刺激血管生成素-1（Ang-1）的表达，血管生成素-1是星形胶质细胞中的一种抗通透性因子。过表达SSeCKS的星形胶质细胞的条件培养基（SSeCKS-CM）在体内和体外均能阻断血管生成。此外，SSeCKS-CM增加了内皮细胞中的紧密连接蛋白，从而降低了[3H]蔗糖的通透性。此外，在血脑屏障成熟期间，对SSeCKS的免疫反应性逐渐增加，并且在体内，表达SSeCKS的星形胶质细胞与表达闭合蛋白（ZO）-1的血管紧密相互作用。总的来说，我们的结果表明，SSeCKS通过调节脑内血管生成和紧密连接的形成来调控血脑屏障的分化。
