Article
Endothelial ephrinB2/EphB4 signaling controls permeability of glioma blood vessels
EphrinB2/EphB4 abhängige Signaltransduktion im Endothel bestimmt die Permeabilität von Blutgefässen im Gliom
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Published: | May 8, 2006 |
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Objective: The receptor tyrosine kinase EphB4 and its ligand ephrinB2 have been suggested to be critical for vascular development. Recently, we have demonstrated that both molecules are expressed within glioma blood vessels. The objective of this study was to address the role of ephrinB2/EphB4 signaling in the regulation of glioma blood vessel permeability.
Methods: To study their role in the regulation of tumor blood vessel permeability, the EphB4 wild type receptor (EphB4wt) and a signaling defective dominant-negative mutant form of EphB4 (EphB4dn) were overexpressed specifically in blood vessels of glioma xenografts using a retroviral approach. Expression of the empty control vector served as control (pLXSN).
Results: Intravital fluorescence microscopy revealed a 20-30% decrease in tumor blood vessel permeability in EphB4wt and EphB4dn transfected vessels. As a potential mechanism RT-PCR demonstrated an increased expression of the vessel stabilizing factor Ang-1 in both groups. In parallel its endothelial receptor Tie2 was characterized by increased phopshorylation and activation levels. In situ hybridization identified pericytes as the source of Ang-1. To gain more insight into the cellular consequences of Ang-1/Tie2 activation, electron microscopic studies of glioma blood vessels were performed. These studies demonstrated a sealing and stabilization of glioma blood vessel via a tight assembly of pericytes to the endothelium.
Conclusions: EphB4 signaling reduces the permeability of glioma blood vessels through a link to the Ang-1/Tie2 system, independently of the EphB4 kinase domain. Intervention with this molecule may provide novel opportunities for the development of anti-glioma strategies.