Thalidomide inhibits angiogenesis in embryoid bodies by the generation of hydroxyl radicals

Citation
H. Sauer et al., Thalidomide inhibits angiogenesis in embryoid bodies by the generation of hydroxyl radicals, AM J PATH, 156(1), 2000, pp. 151-158
Citations number
24
Language
INGLESE
art.tipo
Article
Categorie Soggetti
Research/Laboratory Medicine & Medical Tecnology","Medical Research Diagnosis & Treatment
Journal title
AMERICAN JOURNAL OF PATHOLOGY
ISSN journal
0002-9440 → ACNP
Volume
156
Issue
1
Year of publication
2000
Pages
151 - 158
Database
ISI
SICI code
0002-9440(200001)156:1<151:TIAIEB>2.0.ZU;2-L
Abstract
Thalidomide is a teratogen with anti-angiogenic properties and causes stunt ed limb growth (dysmelia) during human embryogenesis, The molecular mechani sms of thalidomide action in embryopathy are currently unknown. Using the e ndothelial-specific antigen platelet endothelial cell adhesion molecule-1 a nd confocal laser scanning microscopy we have demonstrated that thalidomide exerts anti-angiogenic effects on the development of capillary structures in embryoid bodies differentiated from murine embryonic stem cells. Consequ ently, in thalidomide-treated embryoid bodies the diffusion properties of t he tissue were deteriorated, Thalidomide raised reactive oxygen-species (RO S), as revealed using 2',7'-dichlorodihydrofluorescein diacetate (H2DCF-DA) as an indicator. A comparable ROS generation was achieved with the thalido mide hydrolysis product phthaloyl glutamic acid (PGA), but not with phthali mide (PI), the major component of thalidomide. ROS formation by thalidomide was inhibited by the hydroxyl radical scavengers mannitol and 2-mercaptoet hanol. After coadministration of either 2-mercaptoethanol or mannitol with thalidomide the anti-angiogenic effects of thalidomide were abolished and t he diffusion properties of the tissue were restored to the control values. In summary, our data suggest that thalidomide exerts its anti-angiogenic pr operties via the generation of toxic hydroxyl radicals, which impair vascul ogenesis and angiogenesis during embryoid body development.