VEGF-B inhibits apoptosis via VEGFR-1–mediated suppression of the expression of BH3-only protein genes in mice and rats
Identifieur interne : 000582 ( Pmc/Corpus ); précédent : 000581; suivant : 000583VEGF-B inhibits apoptosis via VEGFR-1–mediated suppression of the expression of BH3-only protein genes in mice and rats
Auteurs : Yang Li ; Fan Zhang ; Nobuo Nagai ; Zhongshu Tang ; Shuihua Zhang ; Pierre Scotney ; Johan Lennartsson ; Chaoyong Zhu ; Yi Qu ; Changge Fang ; Jianyuan Hua ; Osamu Matsuo ; Guo-Hua Fong ; Hao Ding ; Yihai Cao ; Kevin G. Becker ; Andrew Nash ; Carl-Henrik Heldin ; Xuri LiSource :
- The Journal of Clinical Investigation [ 0021-9738 ] ; 2008.
Abstract
Despite its early discovery and high sequence homology to the other VEGF family members, the biological functions of VEGF-B remain poorly understood. We revealed here a novel function for VEGF-B as a potent inhibitor of apoptosis. Using gene expression profiling of mouse primary aortic smooth muscle cells, and confirming the results by real-time PCR using mouse and rat cell lines, we showed that VEGF-B inhibited the expression of genes encoding the proapoptotic BH3-only proteins and other apoptosis- and cell death–related proteins, including p53 and members of the caspase family, via activation of VEGFR-1. Consistent with this, VEGF-B treatment rescued neurons from apoptosis in the retina and brain in mouse models of ocular neurodegenerative disorders and stroke, respectively. Interestingly, VEGF-B treatment at the dose effective for neuronal survival did not cause retinal neovascularization, suggesting that VEGF-B is the first member of the VEGF family that has a potent antiapoptotic effect while lacking a general angiogenic activity. These findings indicate that VEGF-B may potentially offer a new therapeutic option for the treatment of neurodegenerative diseases.
Url:
DOI: 10.1172/JCI33673
PubMed: 18259607
PubMed Central: 2230661
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PMC:2230661Le document en format XML
<record><TEI><teiHeader><fileDesc><titleStmt><title xml:lang="en">VEGF-B inhibits apoptosis via VEGFR-1–mediated suppression of the expression of BH3-only protein genes in mice and rats</title><author><name sortKey="Li, Yang" sort="Li, Yang" uniqKey="Li Y" first="Yang" last="Li">Yang Li</name><affiliation><nlm:aff id="JCI33673">National Eye Institute, NIH, Porter Neuroscience Research Center, Bethesda, Maryland, USA.</nlm:aff></affiliation></author><author><name sortKey="Zhang, Fan" sort="Zhang, Fan" uniqKey="Zhang F" first="Fan" last="Zhang">Fan Zhang</name><affiliation><nlm:aff id="JCI33673">National Eye Institute, NIH, Porter Neuroscience Research Center, Bethesda, Maryland, USA.</nlm:aff></affiliation></author><author><name sortKey="Nagai, Nobuo" sort="Nagai, Nobuo" uniqKey="Nagai N" first="Nobuo" last="Nagai">Nobuo Nagai</name><affiliation><nlm:aff id="JCI33673">Department of Physiology, Kinki University School of Medicine, Osakasayama, Osaka, Japan.</nlm:aff></affiliation></author><author><name sortKey="Tang, Zhongshu" sort="Tang, Zhongshu" uniqKey="Tang Z" first="Zhongshu" last="Tang">Zhongshu Tang</name><affiliation><nlm:aff id="JCI33673">National Eye Institute, NIH, Porter Neuroscience Research Center, Bethesda, Maryland, USA.</nlm:aff></affiliation></author><author><name sortKey="Zhang, Shuihua" sort="Zhang, Shuihua" uniqKey="Zhang S" first="Shuihua" last="Zhang">Shuihua Zhang</name><affiliation><nlm:aff id="JCI33673">National Eye Institute, NIH, Porter Neuroscience Research Center, Bethesda, Maryland, USA.</nlm:aff></affiliation></author><author><name sortKey="Scotney, Pierre" sort="Scotney, Pierre" uniqKey="Scotney P" first="Pierre" last="Scotney">Pierre Scotney</name><affiliation><nlm:aff id="JCI33673">CSL Limited, Parkville, Victoria, Australia.</nlm:aff></affiliation></author><author><name sortKey="Lennartsson, Johan" sort="Lennartsson, Johan" uniqKey="Lennartsson J" first="Johan" last="Lennartsson">Johan Lennartsson</name><affiliation><nlm:aff id="JCI33673">Ludwig Institute for Cancer Research, Uppsala University, Uppsala, Sweden.</nlm:aff></affiliation></author><author><name sortKey="Zhu, Chaoyong" sort="Zhu, Chaoyong" uniqKey="Zhu C" first="Chaoyong" last="Zhu">Chaoyong Zhu</name><affiliation><nlm:aff id="JCI33673">National Eye Institute, NIH, Porter Neuroscience Research Center, Bethesda, Maryland, USA.</nlm:aff></affiliation></author><author><name sortKey="Qu, Yi" sort="Qu, Yi" uniqKey="Qu Y" first="Yi" last="Qu">Yi Qu</name><affiliation><nlm:aff id="JCI33673">National Eye Institute, NIH, Porter Neuroscience Research Center, Bethesda, Maryland, USA.</nlm:aff></affiliation></author><author><name sortKey="Fang, Changge" sort="Fang, Changge" uniqKey="Fang C" first="Changge" last="Fang">Changge Fang</name><affiliation><nlm:aff id="JCI33673">National Eye Institute, NIH, Porter Neuroscience Research Center, Bethesda, Maryland, USA.</nlm:aff></affiliation></author><author><name sortKey="Hua, Jianyuan" sort="Hua, Jianyuan" uniqKey="Hua J" first="Jianyuan" last="Hua">Jianyuan Hua</name><affiliation><nlm:aff id="JCI33673">National Eye Institute, NIH, Porter Neuroscience Research Center, Bethesda, Maryland, USA.</nlm:aff></affiliation></author><author><name sortKey="Matsuo, Osamu" sort="Matsuo, Osamu" uniqKey="Matsuo O" first="Osamu" last="Matsuo">Osamu Matsuo</name><affiliation><nlm:aff id="JCI33673">Department of Physiology, Kinki University School of Medicine, Osakasayama, Osaka, Japan.</nlm:aff></affiliation></author><author><name sortKey="Fong, Guo Hua" sort="Fong, Guo Hua" uniqKey="Fong G" first="Guo-Hua" last="Fong">Guo-Hua Fong</name><affiliation><nlm:aff id="JCI33673">Center for Vascular Biology, University of Connecticut Health Center, Farmington, Connecticut, USA.</nlm:aff></affiliation></author><author><name sortKey="Ding, Hao" sort="Ding, Hao" uniqKey="Ding H" first="Hao" last="Ding">Hao Ding</name><affiliation><nlm:aff id="JCI33673">Department of Biochemistry and Medical Genetics, University of Manitoba, Winnipeg, Manitoba, Canada.</nlm:aff></affiliation></author><author><name sortKey="Cao, Yihai" sort="Cao, Yihai" uniqKey="Cao Y" first="Yihai" last="Cao">Yihai Cao</name><affiliation><nlm:aff id="JCI33673">Department of Microbiology, Tumor and Cell Biology, Karolinska Institute, Stockholm, Sweden.</nlm:aff></affiliation></author><author><name sortKey="Becker, Kevin G" sort="Becker, Kevin G" uniqKey="Becker K" first="Kevin G." last="Becker">Kevin G. Becker</name><affiliation><nlm:aff id="JCI33673">TRIAD Technology Center, National Institute on Aging, NIH, Baltimore, Maryland, USA.</nlm:aff></affiliation></author><author><name sortKey="Nash, Andrew" sort="Nash, Andrew" uniqKey="Nash A" first="Andrew" last="Nash">Andrew Nash</name><affiliation><nlm:aff id="JCI33673">CSL Limited, Parkville, Victoria, Australia.</nlm:aff></affiliation></author><author><name sortKey="Heldin, Carl Henrik" sort="Heldin, Carl Henrik" uniqKey="Heldin C" first="Carl-Henrik" last="Heldin">Carl-Henrik Heldin</name><affiliation><nlm:aff id="JCI33673">Ludwig Institute for Cancer Research, Uppsala University, Uppsala, Sweden.</nlm:aff></affiliation></author><author><name sortKey="Li, Xuri" sort="Li, Xuri" uniqKey="Li X" first="Xuri" last="Li">Xuri Li</name><affiliation><nlm:aff id="JCI33673">National Eye Institute, NIH, Porter Neuroscience Research Center, Bethesda, Maryland, USA.</nlm:aff></affiliation></author></titleStmt><publicationStmt><idno type="wicri:source">PMC</idno><idno type="pmid">18259607</idno><idno type="pmc">2230661</idno><idno type="url">http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2230661</idno><idno type="RBID">PMC:2230661</idno><idno type="doi">10.1172/JCI33673</idno><date when="2008">2008</date><idno type="wicri:Area/Pmc/Corpus">000582</idno><idno type="wicri:explorRef" wicri:stream="Pmc" wicri:step="Corpus" wicri:corpus="PMC">000582</idno></publicationStmt><sourceDesc><biblStruct><analytic><title xml:lang="en" level="a" type="main">VEGF-B inhibits apoptosis via VEGFR-1–mediated suppression of the expression of BH3-only protein genes in mice and rats</title><author><name sortKey="Li, Yang" sort="Li, Yang" uniqKey="Li Y" first="Yang" last="Li">Yang Li</name><affiliation><nlm:aff id="JCI33673">National Eye Institute, NIH, Porter Neuroscience Research Center, Bethesda, Maryland, USA.</nlm:aff></affiliation></author><author><name sortKey="Zhang, Fan" sort="Zhang, Fan" uniqKey="Zhang F" first="Fan" last="Zhang">Fan Zhang</name><affiliation><nlm:aff id="JCI33673">National Eye Institute, NIH, Porter Neuroscience Research Center, Bethesda, Maryland, USA.</nlm:aff></affiliation></author><author><name sortKey="Nagai, Nobuo" sort="Nagai, Nobuo" uniqKey="Nagai N" first="Nobuo" last="Nagai">Nobuo Nagai</name><affiliation><nlm:aff id="JCI33673">Department of Physiology, Kinki University School of Medicine, Osakasayama, Osaka, Japan.</nlm:aff></affiliation></author><author><name sortKey="Tang, Zhongshu" sort="Tang, Zhongshu" uniqKey="Tang Z" first="Zhongshu" last="Tang">Zhongshu Tang</name><affiliation><nlm:aff id="JCI33673">National Eye Institute, NIH, Porter Neuroscience Research Center, Bethesda, Maryland, USA.</nlm:aff></affiliation></author><author><name sortKey="Zhang, Shuihua" sort="Zhang, Shuihua" uniqKey="Zhang S" first="Shuihua" last="Zhang">Shuihua Zhang</name><affiliation><nlm:aff id="JCI33673">National Eye Institute, NIH, Porter Neuroscience Research Center, Bethesda, Maryland, USA.</nlm:aff></affiliation></author><author><name sortKey="Scotney, Pierre" sort="Scotney, Pierre" uniqKey="Scotney P" first="Pierre" last="Scotney">Pierre Scotney</name><affiliation><nlm:aff id="JCI33673">CSL Limited, Parkville, Victoria, Australia.</nlm:aff></affiliation></author><author><name sortKey="Lennartsson, Johan" sort="Lennartsson, Johan" uniqKey="Lennartsson J" first="Johan" last="Lennartsson">Johan Lennartsson</name><affiliation><nlm:aff id="JCI33673">Ludwig Institute for Cancer Research, Uppsala University, Uppsala, Sweden.</nlm:aff></affiliation></author><author><name sortKey="Zhu, Chaoyong" sort="Zhu, Chaoyong" uniqKey="Zhu C" first="Chaoyong" last="Zhu">Chaoyong Zhu</name><affiliation><nlm:aff id="JCI33673">National Eye Institute, NIH, Porter Neuroscience Research Center, Bethesda, Maryland, USA.</nlm:aff></affiliation></author><author><name sortKey="Qu, Yi" sort="Qu, Yi" uniqKey="Qu Y" first="Yi" last="Qu">Yi Qu</name><affiliation><nlm:aff id="JCI33673">National Eye Institute, NIH, Porter Neuroscience Research Center, Bethesda, Maryland, USA.</nlm:aff></affiliation></author><author><name sortKey="Fang, Changge" sort="Fang, Changge" uniqKey="Fang C" first="Changge" last="Fang">Changge Fang</name><affiliation><nlm:aff id="JCI33673">National Eye Institute, NIH, Porter Neuroscience Research Center, Bethesda, Maryland, USA.</nlm:aff></affiliation></author><author><name sortKey="Hua, Jianyuan" sort="Hua, Jianyuan" uniqKey="Hua J" first="Jianyuan" last="Hua">Jianyuan Hua</name><affiliation><nlm:aff id="JCI33673">National Eye Institute, NIH, Porter Neuroscience Research Center, Bethesda, Maryland, USA.</nlm:aff></affiliation></author><author><name sortKey="Matsuo, Osamu" sort="Matsuo, Osamu" uniqKey="Matsuo O" first="Osamu" last="Matsuo">Osamu Matsuo</name><affiliation><nlm:aff id="JCI33673">Department of Physiology, Kinki University School of Medicine, Osakasayama, Osaka, Japan.</nlm:aff></affiliation></author><author><name sortKey="Fong, Guo Hua" sort="Fong, Guo Hua" uniqKey="Fong G" first="Guo-Hua" last="Fong">Guo-Hua Fong</name><affiliation><nlm:aff id="JCI33673">Center for Vascular Biology, University of Connecticut Health Center, Farmington, Connecticut, USA.</nlm:aff></affiliation></author><author><name sortKey="Ding, Hao" sort="Ding, Hao" uniqKey="Ding H" first="Hao" last="Ding">Hao Ding</name><affiliation><nlm:aff id="JCI33673">Department of Biochemistry and Medical Genetics, University of Manitoba, Winnipeg, Manitoba, Canada.</nlm:aff></affiliation></author><author><name sortKey="Cao, Yihai" sort="Cao, Yihai" uniqKey="Cao Y" first="Yihai" last="Cao">Yihai Cao</name><affiliation><nlm:aff id="JCI33673">Department of Microbiology, Tumor and Cell Biology, Karolinska Institute, Stockholm, Sweden.</nlm:aff></affiliation></author><author><name sortKey="Becker, Kevin G" sort="Becker, Kevin G" uniqKey="Becker K" first="Kevin G." last="Becker">Kevin G. Becker</name><affiliation><nlm:aff id="JCI33673">TRIAD Technology Center, National Institute on Aging, NIH, Baltimore, Maryland, USA.</nlm:aff></affiliation></author><author><name sortKey="Nash, Andrew" sort="Nash, Andrew" uniqKey="Nash A" first="Andrew" last="Nash">Andrew Nash</name><affiliation><nlm:aff id="JCI33673">CSL Limited, Parkville, Victoria, Australia.</nlm:aff></affiliation></author><author><name sortKey="Heldin, Carl Henrik" sort="Heldin, Carl Henrik" uniqKey="Heldin C" first="Carl-Henrik" last="Heldin">Carl-Henrik Heldin</name><affiliation><nlm:aff id="JCI33673">Ludwig Institute for Cancer Research, Uppsala University, Uppsala, Sweden.</nlm:aff></affiliation></author><author><name sortKey="Li, Xuri" sort="Li, Xuri" uniqKey="Li X" first="Xuri" last="Li">Xuri Li</name><affiliation><nlm:aff id="JCI33673">National Eye Institute, NIH, Porter Neuroscience Research Center, Bethesda, Maryland, USA.</nlm:aff></affiliation></author></analytic><series><title level="j">The Journal of Clinical Investigation</title><idno type="ISSN">0021-9738</idno><imprint><date when="2008">2008</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en"><p>Despite its early discovery and high sequence homology to the other VEGF family members, the biological functions of VEGF-B remain poorly understood. We revealed here a novel function for VEGF-B as a potent inhibitor of apoptosis. Using gene expression profiling of mouse primary aortic smooth muscle cells, and confirming the results by real-time PCR using mouse and rat cell lines, we showed that VEGF-B inhibited the expression of genes encoding the proapoptotic BH3-only proteins and other apoptosis- and cell death–related proteins, including p53 and members of the caspase family, via activation of VEGFR-1. Consistent with this, VEGF-B treatment rescued neurons from apoptosis in the retina and brain in mouse models of ocular neurodegenerative disorders and stroke, respectively. Interestingly, VEGF-B treatment at the dose effective for neuronal survival did not cause retinal neovascularization, suggesting that VEGF-B is the first member of the VEGF family that has a potent antiapoptotic effect while lacking a general angiogenic activity. These findings indicate that VEGF-B may potentially offer a new therapeutic option for the treatment of neurodegenerative diseases.</p></div></front></TEI><pmc article-type="research-article"><pmc-comment>The publisher of this article does not allow downloading of the full text in XML form.</pmc-comment>
<front><journal-meta><journal-id journal-id-type="nlm-ta">J Clin Invest</journal-id><journal-id journal-id-type="publisher-id">J CLIN INVEST</journal-id><journal-title>The Journal of Clinical Investigation</journal-title><issn pub-type="ppub">0021-9738</issn><publisher><publisher-name>American Society for Clinical Investigation</publisher-name></publisher></journal-meta><article-meta><article-id pub-id-type="pmid">18259607</article-id><article-id pub-id-type="pmc">2230661</article-id><article-id pub-id-type="publisher-id">33673</article-id><article-id pub-id-type="doi">10.1172/JCI33673</article-id><article-categories><subj-group subj-group-type="heading"><subject>Research Article</subject></subj-group></article-categories><title-group><article-title>VEGF-B inhibits apoptosis via VEGFR-1–mediated suppression of the expression of BH3-only protein genes in mice and rats</article-title></title-group><contrib-group><contrib contrib-type="author"><name><surname>Li</surname><given-names>Yang</given-names></name><xref ref-type="aff" rid="JCI33673">1</xref></contrib><contrib contrib-type="author"><name><surname>Zhang</surname><given-names>Fan</given-names></name><xref ref-type="aff" rid="JCI33673">1</xref></contrib><contrib contrib-type="author"><name><surname>Nagai</surname><given-names>Nobuo</given-names></name><xref ref-type="aff" rid="JCI33673">2</xref></contrib><contrib contrib-type="author"><name><surname>Tang</surname><given-names>Zhongshu</given-names></name><xref ref-type="aff" rid="JCI33673">1</xref></contrib><contrib contrib-type="author"><name><surname>Zhang</surname><given-names>Shuihua</given-names></name><xref ref-type="aff" rid="JCI33673">1</xref></contrib><contrib contrib-type="author"><name><surname>Scotney</surname><given-names>Pierre</given-names></name><xref ref-type="aff" rid="JCI33673">3</xref></contrib><contrib contrib-type="author"><name><surname>Lennartsson</surname><given-names>Johan</given-names></name><xref ref-type="aff" rid="JCI33673">4</xref></contrib><contrib contrib-type="author"><name><surname>Zhu</surname><given-names>Chaoyong</given-names></name><xref ref-type="aff" rid="JCI33673">1</xref></contrib><contrib contrib-type="author"><name><surname>Qu</surname><given-names>Yi</given-names></name><xref ref-type="aff" rid="JCI33673">1</xref></contrib><contrib contrib-type="author"><name><surname>Fang</surname><given-names>Changge</given-names></name><xref ref-type="aff" rid="JCI33673">1</xref></contrib><contrib contrib-type="author"><name><surname>Hua</surname><given-names>Jianyuan</given-names></name><xref ref-type="aff" rid="JCI33673">1</xref></contrib><contrib contrib-type="author"><name><surname>Matsuo</surname><given-names>Osamu</given-names></name><xref ref-type="aff" rid="JCI33673">2</xref></contrib><contrib contrib-type="author"><name><surname>Fong</surname><given-names>Guo-Hua</given-names></name><xref ref-type="aff" rid="JCI33673">5</xref></contrib><contrib contrib-type="author"><name><surname>Ding</surname><given-names>Hao</given-names></name><xref ref-type="aff" rid="JCI33673">6</xref></contrib><contrib contrib-type="author"><name><surname>Cao</surname><given-names>Yihai</given-names></name><xref ref-type="aff" rid="JCI33673">7</xref></contrib><contrib contrib-type="author"><name><surname>Becker</surname><given-names>Kevin G.</given-names></name><xref ref-type="aff" rid="JCI33673">8</xref></contrib><contrib contrib-type="author"><name><surname>Nash</surname><given-names>Andrew</given-names></name><xref ref-type="aff" rid="JCI33673">3</xref></contrib><contrib contrib-type="author"><name><surname>Heldin</surname><given-names>Carl-Henrik</given-names></name><xref ref-type="aff" rid="JCI33673">4</xref></contrib><contrib contrib-type="author"><name><surname>Li</surname><given-names>Xuri</given-names></name><xref ref-type="aff" rid="JCI33673">1</xref></contrib></contrib-group><aff id="JCI33673"><label>1</label>National Eye Institute, NIH, Porter Neuroscience Research Center, Bethesda, Maryland, USA.<label>2</label>Department of Physiology, Kinki University School of Medicine, Osakasayama, Osaka, Japan.<label>3</label>CSL Limited, Parkville, Victoria, Australia.<label>4</label>Ludwig Institute for Cancer Research, Uppsala University, Uppsala, Sweden.<label>5</label>Center for Vascular Biology, University of Connecticut Health Center, Farmington, Connecticut, USA.<label>6</label>Department of Biochemistry and Medical Genetics, University of Manitoba, Winnipeg, Manitoba, Canada.<label>7</label>Department of Microbiology, Tumor and Cell Biology, Karolinska Institute, Stockholm, Sweden.<label>8</label>TRIAD Technology Center, National Institute on Aging, NIH, Baltimore, Maryland, USA.</aff><author-notes><corresp>Address correspondence to: Xuri Li, NEI/NIH, Porter Neuroscience Research Center, Building 35, 35 Convent Dr. MSC 3731, Bethesda, Maryland 20892, USA. Phone: (301) 496-4103; Fax: (301) 480-2640; E-mail:
<email>lixur@nei.nih.gov</email>.
</corresp></author-notes><pub-date pub-type="epub"><day>7</day><month>2</month><year>2008</year></pub-date><pub-date pub-type="ppub"><day>3</day><month>3</month><year>2008</year></pub-date><volume>118</volume><issue>3</issue><fpage>913</fpage><lpage>923</lpage><history><date date-type="received"><day>20</day><month>8</month><year>2007</year></date><date date-type="accepted"><day>5</day><month>12</month><year>2007</year></date></history><copyright-statement>Copyright © 2008, American Society for Clinical Investigation</copyright-statement><copyright-year>2008</copyright-year><abstract><p>Despite its early discovery and high sequence homology to the other VEGF family members, the biological functions of VEGF-B remain poorly understood. We revealed here a novel function for VEGF-B as a potent inhibitor of apoptosis. Using gene expression profiling of mouse primary aortic smooth muscle cells, and confirming the results by real-time PCR using mouse and rat cell lines, we showed that VEGF-B inhibited the expression of genes encoding the proapoptotic BH3-only proteins and other apoptosis- and cell death–related proteins, including p53 and members of the caspase family, via activation of VEGFR-1. Consistent with this, VEGF-B treatment rescued neurons from apoptosis in the retina and brain in mouse models of ocular neurodegenerative disorders and stroke, respectively. Interestingly, VEGF-B treatment at the dose effective for neuronal survival did not cause retinal neovascularization, suggesting that VEGF-B is the first member of the VEGF family that has a potent antiapoptotic effect while lacking a general angiogenic activity. These findings indicate that VEGF-B may potentially offer a new therapeutic option for the treatment of neurodegenerative diseases.</p></abstract></article-meta></front><floats-wrap><fig id="F1" position="float"><label>Figure 1</label><caption><title>VEGF-B<sub>167</sub> inhibits the expression of the BH3-only protein and other apoptotic/cell death–related genes in multiple cell lines.
</title><p>(<bold>A</bold>) VEGF-B<sub>167</sub> treatment inhibited the expression of the BH3-only protein (<italic>Bmf</italic>, <italic>Hrk</italic>, <italic>Puma</italic>, <italic>Bid</italic>, <italic>Bik</italic>, <italic>Noxa</italic>) and other apoptotic/cell death–related genes in the rat RGC-derived cell line RGC5 according to real-time PCR assay. (<bold>B</bold>) VEGF-B<sub>167</sub> treatment inhibited the expression of the BH3-only protein (<italic>Hrk</italic>, <italic>Bik</italic>, <italic>Bid</italic>, <italic>Bmf</italic>, <italic>Noxa</italic>) and other apoptotic/cell death–related genes in the immortalized rat retinal pericyte cell line TR-rPCT. (<bold>C</bold>) VEGF-B<sub>167</sub> treatment inhibited the expression of the BH3-only protein (<italic>Bmf</italic>, <italic>Bik</italic>, <italic>Noxa</italic>, <italic>Bid</italic>, <italic>Hrk</italic>) and other apoptotic/cell death–related genes in the immortalized rat retinal Müller cell line TR-MUL. (<bold>D</bold>) VEGF-B<sub>167</sub> treatment inhibited the expression of the BH3-only protein (<italic>Bik</italic>, <italic>Bid</italic>, <italic>Hrk</italic>, <italic>Noxa</italic>, <italic>Puma</italic>) and other apoptotic/cell death–related genes in the immortalized rat retinal endothelial cell line TR-iBRB. (<bold>E</bold>) VEGF-B<sub>167</sub> treatment inhibited the expression of the BH3-only protein (<italic>Bid</italic>, <italic>Bik</italic>, <italic>Bbc3</italic>, <italic>Bad</italic>, <italic>Hrk</italic>, <italic>Noxa</italic>, <italic>Bmf</italic>) and other apoptotic/cell death–related genes in mouse primary aortic smooth muscle cells (mSMC).
</p></caption><graphic xlink:href="JCI0833673.f1"></graphic></fig><fig id="F2" position="float"><label>Figure 2</label><caption><title>Survival effect of VEGF-B on the RGC5 cells.</title><p>(<bold>A</bold> and <bold>B</bold>) H<sub>2</sub>O<sub>2</sub> treatment led to oxidative stress–induced apoptosis in RGC5 cells according to the TUNEL assay. (<bold>C</bold> and <bold>D</bold>) VEGF-B<sub>167</sub> treatment inhibited the H<sub>2</sub>O<sub>2</sub>-induced apoptosis. Scale bar: 50 μm. (<bold>E</bold>) VEGF-B rescued serum deprivation–induced cell death in RGC5 cells at different time points. (<bold>F</bold>) PlGF did not rescue serum deprivation–induced cell death in RGC5 cells at different time points. (<bold>G</bold>) VEGF had a weak survival effect on RGC5 cells. (<bold>H</bold> and <bold>I</bold>) Bmf overexpression in the RGC5 cells led to apoptosis according to the TUNEL assay. (<bold>J</bold> and <bold>K</bold>) VEGF-B<sub>167</sub> treatment inhibited Bmf-induced cellular apoptosis in RGC5 cells. Scale bar: 100 μm. (<bold>L</bold>) VEGF-B<sub>167</sub> treatment inhibited both the endogenous (rat) and exogenous (mouse) Bmf expression in RGC5 cells. *<italic>P < </italic>0.05, **<italic>P < </italic>0.01.
</p></caption><graphic xlink:href="JCI0833673.f2"></graphic></fig><fig id="F3" position="float"><label>Figure 3</label><caption><title>VEGF-B inhibits axotomy-induced apoptosis in the retina.</title><p>(<bold>A</bold>) VEGF-B is highly expressed in the retina as shown by the in situ hybridization assay. A high level of VEGF-B expression was found primarily in the RGCs and the inner and outer nuclear layers (INL and ONL, arrows). VEGFR-1 expression was mainly found in the inner plexiform layer, part of the inner nuclear layer, and the inner and outer segment layers (IS, OS). Scale bar: 50 μm. (<bold>B</bold> and <bold>C</bold>) Real-time PCR assay showed that VEGF-B (<bold>B</bold>) and VEGFR-1 (<bold>C</bold>) expression were upregulated in the retinae after ONC injury. The upregulation was seen as early as 6 hours after ONC and reached a high level after 1 week. (<bold>D</bold>–<bold>F</bold>) A single dose of VEGF-B<sub>167</sub> intravitreal treatment increased the number of viable RGCs by about 1.7-fold. VEGF-B neutralizing antibody intravitreal treatment decreased the number of viable RGCs by about 33% (<bold>F</bold>). VEGFR-1 ECD treatment decreased the number of viable RGCs by about 42% (<bold>F</bold>). Scale bar: 10 μm. (<bold>G</bold>–<bold>J</bold>) Real-time PCR analysis revealed that VEGF-B<sub>167</sub> treatment inhibited the expression of the BH3-only protein genes <italic>Noxa</italic> (<bold>G</bold>) and <italic>Bmf</italic> (<bold>H</bold>), as well as <italic>Bak</italic> (<bold>I</bold>) and <italic>p53</italic> (<bold>J</bold>) expression in both normal and ONC-injured retinae. *<italic>P < </italic>0.05, **<italic>P < </italic>0.01.
</p></caption><graphic xlink:href="JCI0833673.f3"></graphic></fig><fig id="F4" position="float"><label>Figure 4</label><caption><title>VEGF-B inhibits excitotoxin-induced apoptosis in the retina.</title><p>(<bold>A</bold>) NMDA intravitreous treatment led to massive apoptosis in the retina as shown by TUNEL staining. (<bold>B</bold> and <bold>C</bold>) VEGF-B<sub>167</sub> treatment significantly reduced the number of apoptotic cells in all the 3 layers of the retina. Scale bar: 20 μm. (<bold>D</bold>) Real-time PCR assay revealed that VEGF-B<sub>167</sub> treatment inhibited the expression of the BH3-only protein (<italic>Bmf</italic>, <italic>Hrk</italic>, <italic>Bad</italic>, <italic>Bid</italic>, <italic>Bim</italic>) and other apoptotic/cell death–related genes in the NMDA-injured retina. **<italic>P < </italic>0.01, ***<italic>P < </italic>0.001.
</p></caption><graphic xlink:href="JCI0833673.f4"></graphic></fig><fig id="F5" position="float"><label>Figure 5</label><caption><title>VEGF-B inhibits ischemia-induced neuronal apoptosis and apoptotic gene expression in the brain.</title><p>(<bold>A</bold>) VEGF-B expression is upregulated in the border zone of the brain after MCA occlusion as shown by immunohistochemical staining. Scale bar: 50 μm. (<bold>B</bold> and <bold>C</bold>) Recombinant human VEGF-B<sub>167</sub> protein treatment decreased brain damage volume by about 32% in the wild-type mice as shown by the MAP-2 staining. Scale bar: 100 μm. (<bold>D</bold> and <bold>E</bold>) VEGF-B<sub>167</sub> treatment decreased the number of the apoptotic cells in the border zone of the stroke as shown by TUNEL staining. Scale bar: 10 μm. (<bold>F</bold>) VEGF-B<sub>167</sub> treatment inhibited the expression of the BH3-only protein genes <italic>Bmf</italic> and <italic>Hrk</italic> and the apoptotic gene <italic>Trp53inp1</italic> in the brain with stroke.
</p></caption><graphic xlink:href="JCI0833673.f5"></graphic></fig><fig id="F6" position="float"><label>Figure 6</label><caption><title>VEGFR-1 mediates the effect of VEGF-B.</title><p>(<bold>A</bold>) VEGF-B<sub>167</sub> stimulation resulted in VEGFR-1 activation in the bEnd.3 cells and the cortex neurons using the immunoprecipitation assay and anti–VEGFR-1 antibody, followed by the Western blot assay using anti-phosphotyrosine antibody (anti-pTyr). VEGFR-1 was detected in bEnd.3 cells and cortex neurons using Western blot assay. (<bold>B</bold>) VEGF-B<sub>167</sub> induced VEGFR-1 activation in RGC5 cells using Western blot assay and antibodies against phosphotyrosine and VEGFR-1. (<bold>C</bold>) VEGF-B<sub>167</sub> treatment led to ERK1/2 activation in both bEnd.3 cells and cortex neurons using Western blot assay and antibodies against phosphorylated and total ERK1/2. (<bold>D</bold>) VEGF-B treatment induced Akt phosphorylation in TR-iBRB cells using Western blot assay and antibodies against phosphorylated and total Akt. (<bold>E</bold>–<bold>H</bold>) VEGFR-1 neutralizing antibody treatment abolished to various degrees the inhibitory effect of VEGF-B on the expression of <italic>Bmf</italic> (<bold>E</bold>), <italic>Bax</italic> (<bold>F</bold>), <italic>Bik</italic> (<bold>G</bold>), and <italic>Bak1</italic> (<bold>H</bold>) in RGC5 cells. (<bold>I</bold>, <bold>J</bold>, and <bold>L</bold>) VEGF-B protein treatment increased RGC survival in the ONC-injured retina. Scale bar: 20 μm. (<bold>I</bold>, <bold>K</bold>, and <bold>L</bold>) VEGFR-1 neutralizing antibody treatment largely abolished the VEGF-B–induced RGC survival in the ONC-injured retina. *<italic>P < </italic>0.05, **<italic>P < </italic>0.01, ***<italic>P < </italic>0.001.
</p></caption><graphic xlink:href="JCI0833673.f6"></graphic></fig><fig id="F7" position="float"><label>Figure 7</label><caption><title>VEGF-B does not affect retinal angiogenesis after intravitreous injection.</title><p>(<bold>A</bold>–<bold>C</bold>) VEGF-B<sub>167</sub> treatment did not affect blood vessel density and morphology in the retina using IB4 staining. Scale bar: 50 μm. (<bold>D</bold>–<bold>F</bold>) VEGF-B<sub>167</sub> intravitreous administration after laser treatment did not change the CNV area as shown by IB4 staining. Scale bar: 50 μm.
</p></caption><graphic xlink:href="JCI0833673.f7"></graphic></fig><table-wrap id="T1" position="float"><label>Table 1
</label><caption><p>Apoptotic/cell death–related genes downregulated by VEGF-B<sub>167</sub></p></caption><graphic xlink:href="JCI0833673.t1"></graphic></table-wrap><table-wrap id="T2" position="float"><label>Table 2
</label><caption><p>VEGF-B treatment reduces brain damage volume in both VEGF-B–deficient and wild-type mice</p></caption><graphic xlink:href="JCI0833673.t2"></graphic></table-wrap></floats-wrap></pmc></record>Pour manipuler ce document sous Unix (Dilib)
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