Mechanism of dexamethasone suppression of brain tumor-associated vascular permeability in rats. Involvement of the glucocorticoid receptor and vascular permeability factor.
Brain tumor-associated cerebral edema arises because tumor capillaries lack normal blood-brain barrier function; vascular permeability factor (VPF, also known as vascular endothelial growth factor, VEGF) is a likely mediator of this phenomenon. Clinically, dexamethasone reduces brain tumor-associated vascular permeability through poorly understood mechanisms. Our goals were to determine if suppression of permeability by dexamethasone might involve inhibition of VPF action or expression, and if dexamethasone effects in this setting are mediated by the glucocorticoid receptor (GR). In two rat models of permeability (peripheral vascular permeability induced by intradermal injection of 9L glioma cell-conditioned medium or purified VPF, and intracerebral vascular permeability induced by implanted 9L glioma), dexamethasone suppressed permeability in a dose-dependent manner. Since 80% of the permeability-inducing activity in 9L-conditioned medium was removed by anti-VPF antibodies, we examined dexamethasone effects of VPF expression in 9L cells. Dexamethasone inhibited FCS- and PDGF-dependent induction of VPF expression. At all levels (intradermal, intracranial, and cell culture), dexamethasone effects were reversed by the GR antagonist mifepristone (RU486). Dexamethasone may decrease brain tumor-associated vascular permeability by two GR-dependent mechanisms: reduction of the response of the vasculature to tumor-derived permeability factors (including VPF), and reduction of VPF expression by tumor cells.
Heiss
J D
JD
Surgical Neurology Branch, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, Maryland 20892, USA.
Papavassiliou
E
E
Merrill
M J
MJ
Nieman
L
L
Knightly
J J
JJ
Walbridge
S
S
Edwards
N A
NA
Oldfield
E H
EH
D000818:Animals; D019138:Antibodies, Blocking / Q000276:immunology; D015152:Blotting, Northern; D001932:Brain Neoplasms / Q000378:metabolism / Q000503:physiopathology*; D002199:Capillary Permeability; D002478:Cells, Cultured; D017077:Culture Media, Conditioned; D003907:Dexamethasone / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D016228:Endothelial Growth Factors / Q000096:biosynthesis / Q000276:immunology / Q000494:pharmacology; D005910:Glioma / Q000378:metabolism / Q000503:physiopathology; D008222:Lymphokines / Q000096:biosynthesis / Q000276:immunology / Q000494:pharmacology; D015735:Mifepristone / Q000494:pharmacology; D010982:Platelet-Derived Growth Factor / Q000378:metabolism; D051381:Rats; D011965:Receptors, Glucocorticoid / Q000378:metabolism; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors
D019138:Antibodies, Blocking; D017077:Culture Media, Conditioned; D016228:Endothelial Growth Factors; D008222:Lymphokines; D010982:Platelet-Derived Growth Factor; D011965:Receptors, Glucocorticoid; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors; D015735:Mifepristone; D003907:Dexamethasone