Oxygen regulates brain angiogenesis and tight junction formation in blood–brain barrier

Abstract

The maintenance of the blood–brain barrier (BBB) is important in the central nervous system because disruption of the BBB may contribute to many brain disorders, including Alzheimer's disease and stroke. However, the molecular mechanism of brain vessel development and BBB formation remains ill-defined. We found that the immunoreactivities of pimonidazol, hypoxic marker and vascular endothelial growth factor (VEGF) were detected in developing brain, and then disappeared after birth. However, the expression of occludin was gradually increased during BBB maturation. Moreover, we found src-suppressed C-kinase substrate (SSeCKS)-overexpressed in astrocytes during reoxygenation. Overexpressed SSeCKS strongly reduced the VEGF expression and angiogenesis. Furthermore, SSeCKS overexpression increased the expression of both angiopoietin-1 (Ang-1), an antipermeability factor, and tight junction proteins, consequently decreased [3H]sucrose permeability. We therefore conclude that reoxygenation of astrocytes may act as a significant driving force for the BBB maturation, and SSeCKS is a novel regulator of BBB differentiation by modulating both brain angiogenesis and tight junction formation. © 2004, Elsevier Inc. All rights reserved.