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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-associate...
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Published in: | The Journal of clinical investigation 1996-09, Vol.98 (6), p.1400-1408 |
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description | 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. |
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Involvement of the glucocorticoid receptor and vascular permeability factor</title><source>PubMed Central(OpenAccess)</source><source>Free E-Journal (出版社公開部分のみ)</source><creator>Heiss, J D ; Papavassiliou, E ; Merrill, M J ; Nieman, L ; Knightly, J J ; Walbridge, S ; Edwards, N A ; Oldfield, E H</creator><creatorcontrib>Heiss, J D ; Papavassiliou, E ; Merrill, M J ; Nieman, L ; Knightly, J J ; Walbridge, S ; Edwards, N A ; Oldfield, E H</creatorcontrib><description>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.</description><identifier>ISSN: 0021-9738</identifier><identifier>DOI: 10.1172/jci118927</identifier><identifier>PMID: 8823305</identifier><language>eng</language><publisher>United States</publisher><subject>Animals ; Antibodies, Blocking - immunology ; Blotting, Northern ; Brain Neoplasms - metabolism ; Brain Neoplasms - physiopathology ; Capillary Permeability ; Cells, Cultured ; Culture Media, Conditioned ; Dexamethasone - pharmacology ; Dose-Response Relationship, Drug ; Endothelial Growth Factors - biosynthesis ; Endothelial Growth Factors - immunology ; Endothelial Growth Factors - pharmacology ; Glioma - metabolism ; Glioma - physiopathology ; Lymphokines - biosynthesis ; Lymphokines - immunology ; Lymphokines - pharmacology ; Mifepristone - pharmacology ; Platelet-Derived Growth Factor - metabolism ; Rats ; Receptors, Glucocorticoid - metabolism ; Vascular Endothelial Growth Factor A ; Vascular Endothelial Growth Factors</subject><ispartof>The Journal of clinical investigation, 1996-09, Vol.98 (6), p.1400-1408</ispartof><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c475t-e14564a0c4022d5a25509c57463116cedfb50013590f67a0751873b990282a9f3</citedby></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC507566/pdf/$$EPDF$$P50$$Gpubmedcentral$$H</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC507566/$$EHTML$$P50$$Gpubmedcentral$$H</linktohtml><link.rule.ids>230,314,727,780,784,885,27924,27925,53791,53793</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/8823305$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Heiss, J D</creatorcontrib><creatorcontrib>Papavassiliou, E</creatorcontrib><creatorcontrib>Merrill, M J</creatorcontrib><creatorcontrib>Nieman, L</creatorcontrib><creatorcontrib>Knightly, J J</creatorcontrib><creatorcontrib>Walbridge, S</creatorcontrib><creatorcontrib>Edwards, N A</creatorcontrib><creatorcontrib>Oldfield, E H</creatorcontrib><title>Mechanism of dexamethasone suppression of brain tumor-associated vascular permeability in rats. Involvement of the glucocorticoid receptor and vascular permeability factor</title><title>The Journal of clinical investigation</title><addtitle>J Clin Invest</addtitle><description>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.</description><subject>Animals</subject><subject>Antibodies, Blocking - immunology</subject><subject>Blotting, Northern</subject><subject>Brain Neoplasms - metabolism</subject><subject>Brain Neoplasms - physiopathology</subject><subject>Capillary Permeability</subject><subject>Cells, Cultured</subject><subject>Culture Media, Conditioned</subject><subject>Dexamethasone - pharmacology</subject><subject>Dose-Response Relationship, Drug</subject><subject>Endothelial Growth Factors - biosynthesis</subject><subject>Endothelial Growth Factors - immunology</subject><subject>Endothelial Growth Factors - pharmacology</subject><subject>Glioma - metabolism</subject><subject>Glioma - physiopathology</subject><subject>Lymphokines - biosynthesis</subject><subject>Lymphokines - immunology</subject><subject>Lymphokines - pharmacology</subject><subject>Mifepristone - pharmacology</subject><subject>Platelet-Derived Growth Factor - metabolism</subject><subject>Rats</subject><subject>Receptors, Glucocorticoid - metabolism</subject><subject>Vascular Endothelial Growth Factor A</subject><subject>Vascular Endothelial Growth Factors</subject><issn>0021-9738</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>1996</creationdate><recordtype>article</recordtype><recordid>eNp1kb1u3DAQhFnEcPxX-AEMsDKQQg5_RFEqXAQHO7nAgZukJlbUykdDImWSOsTP5JeMDncwkiLVFvPN7GKHkEvObjjX4vOzdZzXjdAfyAljgheNlvVHcprSM2O8LFV5TI7rWkjJ1Al5-4F2A96lkYaedvgbRswbSMEjTfM0RUzJBb8T2wjO0zyPIRaQUrAOMnZ0C8nOA0Q6YRwRWje4_EoXMkJON3Ttt2HY4og-70LyBunTMNtgQ8zOBtfRiBanHCIF_7-0HuwCnJOjHoaEF4d5Rn7d3_1cfSseHr-uV18eCltqlQvkpapKYLZkQnQKhFKssUqXleS8stj1rVo-IVXD-koD04rXWrZNw0QtoOnlGbnd505zO2Jnl9MjDGaKboT4agI486_i3cY8ha1RS1ZVLf7rgz-GlxlTNqNLFocBPIY5GV1LpepKL-CnPWhjSCli_76DM7Mr03xfrfdlLuzV30e9k4cm5R9Z7KHI</recordid><startdate>19960915</startdate><enddate>19960915</enddate><creator>Heiss, J D</creator><creator>Papavassiliou, E</creator><creator>Merrill, M J</creator><creator>Nieman, L</creator><creator>Knightly, J J</creator><creator>Walbridge, S</creator><creator>Edwards, N A</creator><creator>Oldfield, E H</creator><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7X8</scope><scope>5PM</scope></search><sort><creationdate>19960915</creationdate><title>Mechanism of dexamethasone suppression of brain tumor-associated vascular permeability in rats. Involvement of the glucocorticoid receptor and vascular permeability factor</title><author>Heiss, J D ; Papavassiliou, E ; Merrill, M J ; Nieman, L ; Knightly, J J ; Walbridge, S ; Edwards, N A ; Oldfield, E H</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c475t-e14564a0c4022d5a25509c57463116cedfb50013590f67a0751873b990282a9f3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>1996</creationdate><topic>Animals</topic><topic>Antibodies, Blocking - immunology</topic><topic>Blotting, Northern</topic><topic>Brain Neoplasms - metabolism</topic><topic>Brain Neoplasms - physiopathology</topic><topic>Capillary Permeability</topic><topic>Cells, Cultured</topic><topic>Culture Media, Conditioned</topic><topic>Dexamethasone - pharmacology</topic><topic>Dose-Response Relationship, Drug</topic><topic>Endothelial Growth Factors - biosynthesis</topic><topic>Endothelial Growth Factors - immunology</topic><topic>Endothelial Growth Factors - pharmacology</topic><topic>Glioma - metabolism</topic><topic>Glioma - physiopathology</topic><topic>Lymphokines - biosynthesis</topic><topic>Lymphokines - immunology</topic><topic>Lymphokines - pharmacology</topic><topic>Mifepristone - pharmacology</topic><topic>Platelet-Derived Growth Factor - metabolism</topic><topic>Rats</topic><topic>Receptors, Glucocorticoid - metabolism</topic><topic>Vascular Endothelial Growth Factor A</topic><topic>Vascular Endothelial Growth Factors</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Heiss, J D</creatorcontrib><creatorcontrib>Papavassiliou, E</creatorcontrib><creatorcontrib>Merrill, M J</creatorcontrib><creatorcontrib>Nieman, L</creatorcontrib><creatorcontrib>Knightly, J J</creatorcontrib><creatorcontrib>Walbridge, S</creatorcontrib><creatorcontrib>Edwards, N A</creatorcontrib><creatorcontrib>Oldfield, E H</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>MEDLINE - Academic</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>The Journal of clinical investigation</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Heiss, J D</au><au>Papavassiliou, E</au><au>Merrill, M J</au><au>Nieman, L</au><au>Knightly, J J</au><au>Walbridge, S</au><au>Edwards, N A</au><au>Oldfield, E H</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Mechanism of dexamethasone suppression of brain tumor-associated vascular permeability in rats. Involvement of the glucocorticoid receptor and vascular permeability factor</atitle><jtitle>The Journal of clinical investigation</jtitle><addtitle>J Clin Invest</addtitle><date>1996-09-15</date><risdate>1996</risdate><volume>98</volume><issue>6</issue><spage>1400</spage><epage>1408</epage><pages>1400-1408</pages><issn>0021-9738</issn><abstract>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). 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subjects | Animals Antibodies, Blocking - immunology Blotting, Northern Brain Neoplasms - metabolism Brain Neoplasms - physiopathology Capillary Permeability Cells, Cultured Culture Media, Conditioned Dexamethasone - pharmacology Dose-Response Relationship, Drug Endothelial Growth Factors - biosynthesis Endothelial Growth Factors - immunology Endothelial Growth Factors - pharmacology Glioma - metabolism Glioma - physiopathology Lymphokines - biosynthesis Lymphokines - immunology Lymphokines - pharmacology Mifepristone - pharmacology Platelet-Derived Growth Factor - metabolism Rats Receptors, Glucocorticoid - metabolism Vascular Endothelial Growth Factor A Vascular Endothelial Growth Factors |
title | Mechanism of dexamethasone suppression of brain tumor-associated vascular permeability in rats. Involvement of the glucocorticoid receptor and vascular permeability factor |
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