VEGF-mediated disruption of endothelial CLN-5 promotes blood-brain barrier breakdown
Breakdown of the blood-brain barrier (BBB) is an early and significant event in CNS inflammation. Astrocyte-derived VEGF-A has been implicated in this response, but the underlying mechanisms remain unresolved. Here, we identify the endothelial transmembrane tight junction proteins claudin-5 (CLN-5)...
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| Veröffentlicht in: | Proceedings of the National Academy of Sciences - PNAS 2009-02, Vol.106 (6), p.1977-1982 |
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| container_end_page | 1982 |
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| container_issue | 6 |
| container_start_page | 1977 |
| container_title | Proceedings of the National Academy of Sciences - PNAS |
| container_volume | 106 |
| creator | Argaw, Azeb Tadesse Gurfein, Blake T Zhang, Yueting Zameer, Andleeb John, Gareth R |
| description | Breakdown of the blood-brain barrier (BBB) is an early and significant event in CNS inflammation. Astrocyte-derived VEGF-A has been implicated in this response, but the underlying mechanisms remain unresolved. Here, we identify the endothelial transmembrane tight junction proteins claudin-5 (CLN-5) and occludin (OCLN) as targets of VEGF-A action. Down-regulation of CLN-5 and OCLN accompanied up-regulation of VEGF-A and correlated with BBB breakdown in experimental autoimmune encephalomyelitis, an animal model of CNS inflammatory disease. In cultures of brain microvascular endothelial cells, VEGF-A specifically down-regulated CLN-5 and OCLN protein and mRNA. In mouse cerebral cortex, microinjection of VEGF-A disrupted CLN-5 and OCLN and induced loss of barrier function. Importantly, functional studies revealed that expression of recombinant CLN-5 protected brain microvascular endothelial cell cultures from a VEGF-induced increase in paracellular permeability, whereas recombinant OCLN expressed under the same promoter was not protective. Previous studies have shown CLN-5 to be a key determinant of trans-endothelial resistance at the BBB. Our findings suggest that its down-regulation by VEGF-A constitutes a significant mechanism in BBB breakdown. |
| doi_str_mv | 10.1073/pnas.0808698106 |
| format | Article |
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Astrocyte-derived VEGF-A has been implicated in this response, but the underlying mechanisms remain unresolved. Here, we identify the endothelial transmembrane tight junction proteins claudin-5 (CLN-5) and occludin (OCLN) as targets of VEGF-A action. Down-regulation of CLN-5 and OCLN accompanied up-regulation of VEGF-A and correlated with BBB breakdown in experimental autoimmune encephalomyelitis, an animal model of CNS inflammatory disease. In cultures of brain microvascular endothelial cells, VEGF-A specifically down-regulated CLN-5 and OCLN protein and mRNA. In mouse cerebral cortex, microinjection of VEGF-A disrupted CLN-5 and OCLN and induced loss of barrier function. Importantly, functional studies revealed that expression of recombinant CLN-5 protected brain microvascular endothelial cell cultures from a VEGF-induced increase in paracellular permeability, whereas recombinant OCLN expressed under the same promoter was not protective. Previous studies have shown CLN-5 to be a key determinant of trans-endothelial resistance at the BBB. Our findings suggest that its down-regulation by VEGF-A constitutes a significant mechanism in BBB breakdown.</description><identifier>ISSN: 0027-8424</identifier><identifier>EISSN: 1091-6490</identifier><identifier>DOI: 10.1073/pnas.0808698106</identifier><identifier>PMID: 19174516</identifier><language>eng</language><publisher>United States: National Academy of Sciences</publisher><subject>Animals ; Astrocytes ; Biological Sciences ; Blood ; Blood brain barrier ; Blood-Brain Barrier - metabolism ; Blood-Brain Barrier - pathology ; Brain ; Cattle ; Cell culture ; Cell lines ; Cell Membrane Permeability ; Cells, Cultured ; Central nervous system ; Central Nervous System - pathology ; Cerebral Cortex ; Disease Models, Animal ; Down regulation ; Down-Regulation - genetics ; Encephalomyelitis, Autoimmune, Experimental - pathology ; Endothelial cells ; Endothelium, Vascular - cytology ; Epithelial cells ; Gene expression ; Humans ; Inflammation ; Inflammatory diseases ; Lysosomal Membrane Proteins ; Membrane Proteins - genetics ; Membrane Proteins - physiology ; Membranes ; Mice ; Nervous system ; Occludin ; Proteins ; Spinal cord ; Tight junctions ; Vascular Endothelial Growth Factor A - pharmacology</subject><ispartof>Proceedings of the National Academy of Sciences - PNAS, 2009-02, Vol.106 (6), p.1977-1982</ispartof><rights>Copyright National Academy of Sciences Feb 10, 2009</rights><rights>2009 by The National Academy of Sciences of the USA</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c616t-a5b935243213ea32dedeba1926efc1b81445d34ee677483f5357bf14573e68003</citedby><cites>FETCH-LOGICAL-c616t-a5b935243213ea32dedeba1926efc1b81445d34ee677483f5357bf14573e68003</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Uhttp://www.pnas.org/content/106/6.cover.gif</thumbnail><linktopdf>$$Uhttps://www.jstor.org/stable/pdf/40421708$$EPDF$$P50$$Gjstor$$H</linktopdf><linktohtml>$$Uhttps://www.jstor.org/stable/40421708$$EHTML$$P50$$Gjstor$$H</linktohtml><link.rule.ids>230,314,723,776,780,799,881,27901,27902,53766,53768,57992,58225</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/19174516$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Argaw, Azeb Tadesse</creatorcontrib><creatorcontrib>Gurfein, Blake T</creatorcontrib><creatorcontrib>Zhang, Yueting</creatorcontrib><creatorcontrib>Zameer, Andleeb</creatorcontrib><creatorcontrib>John, Gareth R</creatorcontrib><title>VEGF-mediated disruption of endothelial CLN-5 promotes blood-brain barrier breakdown</title><title>Proceedings of the National Academy of Sciences - PNAS</title><addtitle>Proc Natl Acad Sci U S A</addtitle><description>Breakdown of the blood-brain barrier (BBB) is an early and significant event in CNS inflammation. Astrocyte-derived VEGF-A has been implicated in this response, but the underlying mechanisms remain unresolved. Here, we identify the endothelial transmembrane tight junction proteins claudin-5 (CLN-5) and occludin (OCLN) as targets of VEGF-A action. Down-regulation of CLN-5 and OCLN accompanied up-regulation of VEGF-A and correlated with BBB breakdown in experimental autoimmune encephalomyelitis, an animal model of CNS inflammatory disease. In cultures of brain microvascular endothelial cells, VEGF-A specifically down-regulated CLN-5 and OCLN protein and mRNA. In mouse cerebral cortex, microinjection of VEGF-A disrupted CLN-5 and OCLN and induced loss of barrier function. Importantly, functional studies revealed that expression of recombinant CLN-5 protected brain microvascular endothelial cell cultures from a VEGF-induced increase in paracellular permeability, whereas recombinant OCLN expressed under the same promoter was not protective. Previous studies have shown CLN-5 to be a key determinant of trans-endothelial resistance at the BBB. Our findings suggest that its down-regulation by VEGF-A constitutes a significant mechanism in BBB breakdown.</description><subject>Animals</subject><subject>Astrocytes</subject><subject>Biological Sciences</subject><subject>Blood</subject><subject>Blood brain barrier</subject><subject>Blood-Brain Barrier - metabolism</subject><subject>Blood-Brain Barrier - pathology</subject><subject>Brain</subject><subject>Cattle</subject><subject>Cell culture</subject><subject>Cell lines</subject><subject>Cell Membrane Permeability</subject><subject>Cells, Cultured</subject><subject>Central nervous system</subject><subject>Central Nervous System - pathology</subject><subject>Cerebral Cortex</subject><subject>Disease Models, Animal</subject><subject>Down regulation</subject><subject>Down-Regulation - genetics</subject><subject>Encephalomyelitis, Autoimmune, Experimental - pathology</subject><subject>Endothelial cells</subject><subject>Endothelium, Vascular - cytology</subject><subject>Epithelial cells</subject><subject>Gene expression</subject><subject>Humans</subject><subject>Inflammation</subject><subject>Inflammatory diseases</subject><subject>Lysosomal Membrane Proteins</subject><subject>Membrane Proteins - genetics</subject><subject>Membrane Proteins - physiology</subject><subject>Membranes</subject><subject>Mice</subject><subject>Nervous system</subject><subject>Occludin</subject><subject>Proteins</subject><subject>Spinal cord</subject><subject>Tight junctions</subject><subject>Vascular Endothelial Growth Factor A - pharmacology</subject><issn>0027-8424</issn><issn>1091-6490</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2009</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNqFkb1v1EAQxS0EIkegpgIsCqiczOyXvQ0SOiUB6QQFCe1qbY-TPXxeZ9fm479nT3fKBYRENcX7zdO8eVn2HOEEoeSn42DjCVRQKV0hqAfZAkFjoYSGh9kCgJVFJZg4yp7EuAYALSt4nB2hxlJIVIvs8uvZxXmxodbZidq8dTHM4-T8kPsup6H10w31zvb5cvWpkPkY_MZPFPO6974t6mDdkNc2BEchrwPZb63_MTzNHnW2j_RsP4-zq_Ozy-WHYvX54uPy_apoFKqpsLLWXDLBGXKynLXUUm1RM0Vdg3WFQsiWCyJVlqLineSyrDsUsuSkKgB-nL3b-Y5znSI0NEzB9mYMbmPDL-OtM38qg7sx1_67YUoIFDoZvNkbBH87U5zMxsWG-t4O5OdolNKIgrH_ggxSBoHbk17_Ba79HIb0hcQkK1BaJuh0BzXBxxiouzsZwWx7NdtezaHXtPHyftIDvy8yAW_3wHbzYKeMSlBZmm7u-4l-Tves_k0m4MUOWMfJhztCgGBYQpX0Vzu9s97Y6-CiufqSwnFAqXn6F_8NCTbIZA</recordid><startdate>20090210</startdate><enddate>20090210</enddate><creator>Argaw, Azeb Tadesse</creator><creator>Gurfein, Blake T</creator><creator>Zhang, Yueting</creator><creator>Zameer, Andleeb</creator><creator>John, Gareth R</creator><general>National Academy of Sciences</general><general>National Acad Sciences</general><scope>FBQ</scope><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>7QG</scope><scope>7QL</scope><scope>7QP</scope><scope>7QR</scope><scope>7SN</scope><scope>7SS</scope><scope>7T5</scope><scope>7TK</scope><scope>7TM</scope><scope>7TO</scope><scope>7U9</scope><scope>8FD</scope><scope>C1K</scope><scope>FR3</scope><scope>H94</scope><scope>M7N</scope><scope>P64</scope><scope>RC3</scope><scope>7X8</scope><scope>5PM</scope></search><sort><creationdate>20090210</creationdate><title>VEGF-mediated disruption of endothelial CLN-5 promotes blood-brain barrier breakdown</title><author>Argaw, Azeb Tadesse ; 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Astrocyte-derived VEGF-A has been implicated in this response, but the underlying mechanisms remain unresolved. Here, we identify the endothelial transmembrane tight junction proteins claudin-5 (CLN-5) and occludin (OCLN) as targets of VEGF-A action. Down-regulation of CLN-5 and OCLN accompanied up-regulation of VEGF-A and correlated with BBB breakdown in experimental autoimmune encephalomyelitis, an animal model of CNS inflammatory disease. In cultures of brain microvascular endothelial cells, VEGF-A specifically down-regulated CLN-5 and OCLN protein and mRNA. In mouse cerebral cortex, microinjection of VEGF-A disrupted CLN-5 and OCLN and induced loss of barrier function. Importantly, functional studies revealed that expression of recombinant CLN-5 protected brain microvascular endothelial cell cultures from a VEGF-induced increase in paracellular permeability, whereas recombinant OCLN expressed under the same promoter was not protective. Previous studies have shown CLN-5 to be a key determinant of trans-endothelial resistance at the BBB. Our findings suggest that its down-regulation by VEGF-A constitutes a significant mechanism in BBB breakdown.</abstract><cop>United States</cop><pub>National Academy of Sciences</pub><pmid>19174516</pmid><doi>10.1073/pnas.0808698106</doi><tpages>6</tpages><oa>free_for_read</oa></addata></record> |
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| source | Jstor Complete Legacy; MEDLINE; PubMed Central; Alma/SFX Local Collection; Free Full-Text Journals in Chemistry |
| subjects | Animals Astrocytes Biological Sciences Blood Blood brain barrier Blood-Brain Barrier - metabolism Blood-Brain Barrier - pathology Brain Cattle Cell culture Cell lines Cell Membrane Permeability Cells, Cultured Central nervous system Central Nervous System - pathology Cerebral Cortex Disease Models, Animal Down regulation Down-Regulation - genetics Encephalomyelitis, Autoimmune, Experimental - pathology Endothelial cells Endothelium, Vascular - cytology Epithelial cells Gene expression Humans Inflammation Inflammatory diseases Lysosomal Membrane Proteins Membrane Proteins - genetics Membrane Proteins - physiology Membranes Mice Nervous system Occludin Proteins Spinal cord Tight junctions Vascular Endothelial Growth Factor A - pharmacology |
| title | VEGF-mediated disruption of endothelial CLN-5 promotes blood-brain barrier breakdown |
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