VEGF-B is dispensable for blood vessel growth but critical for their survival, and VEGF-B targeting inhibits pathological angiogenesis
Identifieur interne : 001985 ( Pmc/Curation ); précédent : 001984; suivant : 001986VEGF-B is dispensable for blood vessel growth but critical for their survival, and VEGF-B targeting inhibits pathological angiogenesis
Auteurs : Fan Zhang [États-Unis] ; Zhongshu Tang [États-Unis] ; Xu Hou [États-Unis] ; Johan Lennartsson [Suède] ; Yang Li [États-Unis] ; Alexander W. Koch [États-Unis] ; Pierre Scotney [Australie] ; Chunsik Lee [États-Unis] ; Pachiappan Arjunan [États-Unis] ; Lijin Dong [États-Unis] ; Anil Kumar [États-Unis] ; Tuomas T. Rissanen [Finlande] ; Bin Wang [République populaire de Chine] ; Nobuo Nagai [Japon] ; Pierre Fons [France] ; Robert Fariss [États-Unis] ; Yongqing Zhang [États-Unis] ; Eric Wawrousek [États-Unis] ; Ginger Tansey [États-Unis] ; James Raber [États-Unis] ; Guo-Hua Fong [États-Unis] ; Hao Ding [Canada] ; David A. Greenberg [États-Unis] ; Kevin G. Becker [États-Unis] ; Jean-Marc Herbert [France] ; Andrew Nash [Australie] ; Seppo Yla-Herttuala [Finlande] ; Yihai Cao [Suède] ; Ryan J. Watts [États-Unis] ; Xuri Li [États-Unis]Source :
- Proceedings of the National Academy of Sciences of the United States of America [ 0027-8424 ] ; 2009.
Abstract
VEGF-B, a homolog of VEGF discovered a long time ago, has not been considered an important target in antiangiogenic therapy. Instead, it has received little attention from the field. In this study, using different animal models and multiple types of vascular cells, we revealed that although VEGF-B is dispensable for blood vessel growth, it is critical for their survival. Importantly, the survival effect of VEGF-B is not only on vascular endothelial cells, but also on pericytes, smooth muscle cells, and vascular stem/progenitor cells. In vivo, VEGF-B targeting inhibited both choroidal and retinal neovascularization. Mechanistically, we found that the vascular survival effect of VEGF-B is achieved by regulating the expression of many vascular prosurvival genes via both NP-1 and VEGFR-1. Our work thus indicates that the function of VEGF-B in the vascular system is to act as a “survival,” rather than an “angiogenic” factor and that VEGF-B inhibition may offer new therapeutic opportunities to treat neovascular diseases.
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DOI: 10.1073/pnas.0813061106
PubMed: 19369214
PubMed Central: 2669337
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Biochemistry and Medical Genetics, University of Manitoba, Winnipeg, Canada MB R3E 3P5;</nlm:aff><country>Canada</country><wicri:regionArea>Department of Biochemistry and Medical Genetics, University of Manitoba, Winnipeg</wicri:regionArea></affiliation></author><author><name sortKey="Greenberg, David A" sort="Greenberg, David A" uniqKey="Greenberg D" first="David A." last="Greenberg">David A. Greenberg</name><affiliation wicri:level="2"><nlm:aff wicri:cut="; and" id="aff12">Buck Institute for Age Research, Novato, CA 94945</nlm:aff><country xml:lang="fr">États-Unis</country><placeName><region type="state">Californie</region></placeName><wicri:cityArea>Buck Institute for Age Research, Novato</wicri:cityArea></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 wicri:level="2"><nlm:aff id="aff9">TRIAD Technology Center, National Institute on Aging, National Institutes of Health, Baltimore, MD 21224;</nlm:aff><country xml:lang="fr">États-Unis</country><placeName><region type="state">Maryland</region></placeName><wicri:cityArea>TRIAD Technology Center, National Institute on Aging, National Institutes of Health, Baltimore</wicri:cityArea></affiliation></author><author><name sortKey="Herbert, Jean Marc" sort="Herbert, Jean Marc" uniqKey="Herbert J" first="Jean-Marc" last="Herbert">Jean-Marc Herbert</name><affiliation wicri:level="1"><nlm:aff id="aff8">Sanofi-Aventis Recherche, Cardiovascular-Thrombosis Research Department, 31036 Toulouse Cedex, France;</nlm:aff><country xml:lang="fr">France</country><wicri:regionArea>Sanofi-Aventis Recherche, Cardiovascular-Thrombosis Research Department, 31036 Toulouse Cedex</wicri:regionArea></affiliation></author><author><name sortKey="Nash, Andrew" sort="Nash, Andrew" uniqKey="Nash A" first="Andrew" last="Nash">Andrew Nash</name><affiliation wicri:level="1"><nlm:aff id="aff4">CSL Limited, Parkville, Victoria 3052, Australia;</nlm:aff><country xml:lang="fr">Australie</country><wicri:regionArea>CSL Limited, Parkville, Victoria 3052</wicri:regionArea></affiliation></author><author><name sortKey="Yla Herttuala, Seppo" sort="Yla Herttuala, Seppo" uniqKey="Yla Herttuala S" first="Seppo" last="Yla-Herttuala">Seppo Yla-Herttuala</name><affiliation wicri:level="1"><nlm:aff id="aff5">Department of Biotechnology and Molecular Medicine, University of Kuopio, FIN-70211, Kuopio, Finland;</nlm:aff><country xml:lang="fr">Finlande</country><wicri:regionArea>Department of Biotechnology and Molecular Medicine, University of Kuopio, FIN-70211, Kuopio</wicri:regionArea></affiliation></author><author><name sortKey="Cao, Yihai" sort="Cao, Yihai" uniqKey="Cao Y" first="Yihai" last="Cao">Yihai Cao</name><affiliation wicri:level="1"><nlm:aff id="aff13">Department of Microbiology, Karolinska Institute, 171 77 Stockholm, Sweden</nlm:aff><country xml:lang="fr">Suède</country><wicri:regionArea>Department of Microbiology, Karolinska Institute, 171 77 Stockholm</wicri:regionArea></affiliation></author><author><name sortKey="Watts, Ryan J" sort="Watts, Ryan J" uniqKey="Watts R" first="Ryan J." last="Watts">Ryan J. Watts</name><affiliation wicri:level="2"><nlm:aff id="aff3">Neurodegeneration Labs, Protein Chemistry, Genentech, Inc. San Francisco, CA 94080;</nlm:aff><country xml:lang="fr">États-Unis</country><placeName><region type="state">Californie</region></placeName><wicri:cityArea>Neurodegeneration Labs, Protein Chemistry, Genentech, Inc. San Francisco</wicri:cityArea></affiliation></author><author><name sortKey="Li, Xuri" sort="Li, Xuri" uniqKey="Li X" first="Xuri" last="Li">Xuri Li</name><affiliation wicri:level="2"><nlm:aff id="aff1">National Eye Institute, National Institutes of Health, Bethesda, MD 20892;</nlm:aff><country xml:lang="fr">États-Unis</country><placeName><region type="state">Maryland</region></placeName><wicri:cityArea>National Eye Institute, National Institutes of Health, Bethesda</wicri:cityArea></affiliation></author></titleStmt><publicationStmt><idno type="wicri:source">PMC</idno><idno type="pmid">19369214</idno><idno type="pmc">2669337</idno><idno type="url">http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2669337</idno><idno type="RBID">PMC:2669337</idno><idno type="doi">10.1073/pnas.0813061106</idno><date when="2009">2009</date><idno type="wicri:Area/Pmc/Corpus">001B27</idno><idno type="wicri:explorRef" wicri:stream="Pmc" wicri:step="Corpus" wicri:corpus="PMC">001B27</idno><idno type="wicri:Area/Pmc/Curation">001985</idno><idno type="wicri:explorRef" wicri:stream="Pmc" wicri:step="Curation">001985</idno></publicationStmt><sourceDesc><biblStruct><analytic><title xml:lang="en" level="a" type="main">VEGF-B is dispensable for blood vessel growth but critical for their survival, and VEGF-B targeting inhibits pathological angiogenesis</title><author><name sortKey="Zhang, Fan" sort="Zhang, Fan" uniqKey="Zhang F" first="Fan" last="Zhang">Fan Zhang</name><affiliation wicri:level="2"><nlm:aff id="aff1">National Eye Institute, National Institutes of Health, Bethesda, MD 20892;</nlm:aff><country xml:lang="fr">États-Unis</country><placeName><region type="state">Maryland</region></placeName><wicri:cityArea>National Eye Institute, National Institutes of Health, Bethesda</wicri:cityArea></affiliation></author><author><name sortKey="Tang, Zhongshu" sort="Tang, Zhongshu" uniqKey="Tang Z" first="Zhongshu" last="Tang">Zhongshu Tang</name><affiliation wicri:level="2"><nlm:aff id="aff1">National Eye Institute, National Institutes of Health, Bethesda, MD 20892;</nlm:aff><country xml:lang="fr">États-Unis</country><placeName><region type="state">Maryland</region></placeName><wicri:cityArea>National Eye Institute, National Institutes of Health, Bethesda</wicri:cityArea></affiliation></author><author><name sortKey="Hou, Xu" sort="Hou, Xu" uniqKey="Hou X" first="Xu" last="Hou">Xu Hou</name><affiliation wicri:level="2"><nlm:aff id="aff1">National Eye Institute, National Institutes of Health, Bethesda, MD 20892;</nlm:aff><country xml:lang="fr">États-Unis</country><placeName><region type="state">Maryland</region></placeName><wicri:cityArea>National Eye Institute, National Institutes of Health, Bethesda</wicri:cityArea></affiliation></author><author><name sortKey="Lennartsson, Johan" sort="Lennartsson, Johan" uniqKey="Lennartsson J" first="Johan" last="Lennartsson">Johan Lennartsson</name><affiliation wicri:level="1"><nlm:aff id="aff2">Ludwig Institute for Cancer Research, Uppsala University, SE-751 24 Uppsala, Sweden;</nlm:aff><country xml:lang="fr">Suède</country><wicri:regionArea>Ludwig Institute for Cancer Research, Uppsala University, SE-751 24 Uppsala</wicri:regionArea></affiliation></author><author><name sortKey="Li, Yang" sort="Li, Yang" uniqKey="Li Y" first="Yang" last="Li">Yang Li</name><affiliation wicri:level="2"><nlm:aff id="aff1">National Eye Institute, National Institutes of Health, Bethesda, MD 20892;</nlm:aff><country xml:lang="fr">États-Unis</country><placeName><region type="state">Maryland</region></placeName><wicri:cityArea>National Eye Institute, National Institutes of Health, Bethesda</wicri:cityArea></affiliation></author><author><name sortKey="Koch, Alexander W" sort="Koch, Alexander W" uniqKey="Koch A" first="Alexander W." last="Koch">Alexander W. Koch</name><affiliation wicri:level="2"><nlm:aff id="aff3">Neurodegeneration Labs, Protein Chemistry, Genentech, Inc. San Francisco, CA 94080;</nlm:aff><country xml:lang="fr">États-Unis</country><placeName><region type="state">Californie</region></placeName><wicri:cityArea>Neurodegeneration Labs, Protein Chemistry, Genentech, Inc. San Francisco</wicri:cityArea></affiliation></author><author><name sortKey="Scotney, Pierre" sort="Scotney, Pierre" uniqKey="Scotney P" first="Pierre" last="Scotney">Pierre Scotney</name><affiliation wicri:level="1"><nlm:aff id="aff4">CSL Limited, Parkville, Victoria 3052, Australia;</nlm:aff><country xml:lang="fr">Australie</country><wicri:regionArea>CSL Limited, Parkville, Victoria 3052</wicri:regionArea></affiliation></author><author><name sortKey="Lee, Chunsik" sort="Lee, Chunsik" uniqKey="Lee C" first="Chunsik" last="Lee">Chunsik Lee</name><affiliation wicri:level="2"><nlm:aff id="aff1">National Eye Institute, National Institutes of Health, Bethesda, MD 20892;</nlm:aff><country xml:lang="fr">États-Unis</country><placeName><region type="state">Maryland</region></placeName><wicri:cityArea>National Eye Institute, National Institutes of Health, Bethesda</wicri:cityArea></affiliation></author><author><name sortKey="Arjunan, Pachiappan" sort="Arjunan, Pachiappan" uniqKey="Arjunan P" first="Pachiappan" last="Arjunan">Pachiappan Arjunan</name><affiliation wicri:level="2"><nlm:aff id="aff1">National Eye Institute, National Institutes of Health, Bethesda, MD 20892;</nlm:aff><country xml:lang="fr">États-Unis</country><placeName><region type="state">Maryland</region></placeName><wicri:cityArea>National Eye Institute, National Institutes of Health, Bethesda</wicri:cityArea></affiliation></author><author><name sortKey="Dong, Lijin" sort="Dong, Lijin" uniqKey="Dong L" first="Lijin" last="Dong">Lijin Dong</name><affiliation wicri:level="2"><nlm:aff id="aff1">National Eye Institute, National Institutes of Health, Bethesda, MD 20892;</nlm:aff><country xml:lang="fr">États-Unis</country><placeName><region type="state">Maryland</region></placeName><wicri:cityArea>National Eye Institute, National Institutes of Health, Bethesda</wicri:cityArea></affiliation></author><author><name sortKey="Kumar, Anil" sort="Kumar, Anil" uniqKey="Kumar A" first="Anil" last="Kumar">Anil Kumar</name><affiliation wicri:level="2"><nlm:aff id="aff1">National Eye Institute, National Institutes of Health, Bethesda, MD 20892;</nlm:aff><country xml:lang="fr">États-Unis</country><placeName><region type="state">Maryland</region></placeName><wicri:cityArea>National Eye Institute, National Institutes of Health, Bethesda</wicri:cityArea></affiliation></author><author><name sortKey="Rissanen, Tuomas T" sort="Rissanen, Tuomas T" uniqKey="Rissanen T" first="Tuomas T." last="Rissanen">Tuomas T. Rissanen</name><affiliation wicri:level="1"><nlm:aff id="aff5">Department of Biotechnology and Molecular Medicine, University of Kuopio, FIN-70211, Kuopio, Finland;</nlm:aff><country xml:lang="fr">Finlande</country><wicri:regionArea>Department of Biotechnology and Molecular Medicine, University of Kuopio, FIN-70211, Kuopio</wicri:regionArea></affiliation></author><author><name sortKey="Wang, Bin" sort="Wang, Bin" uniqKey="Wang B" first="Bin" last="Wang">Bin Wang</name><affiliation wicri:level="1"><nlm:aff id="aff6">Department of Radiology, Medical Imaging Centre of the Affiliated Hospital, Weifang Medical University, Weifang 261042, China;</nlm:aff><country xml:lang="fr">République populaire de Chine</country><wicri:regionArea>Department of Radiology, Medical Imaging Centre of the Affiliated Hospital, Weifang Medical University, Weifang 261042</wicri:regionArea></affiliation></author><author><name sortKey="Nagai, Nobuo" sort="Nagai, Nobuo" uniqKey="Nagai N" first="Nobuo" last="Nagai">Nobuo Nagai</name><affiliation wicri:level="1"><nlm:aff id="aff7">Department of Physiology, Kinki University School of Medicine, Osaka 589-8511, Japan;</nlm:aff><country xml:lang="fr">Japon</country><wicri:regionArea>Department of Physiology, Kinki University School of Medicine, Osaka 589-8511</wicri:regionArea></affiliation></author><author><name sortKey="Fons, Pierre" sort="Fons, Pierre" uniqKey="Fons P" first="Pierre" last="Fons">Pierre Fons</name><affiliation wicri:level="1"><nlm:aff id="aff8">Sanofi-Aventis Recherche, Cardiovascular-Thrombosis Research Department, 31036 Toulouse Cedex, France;</nlm:aff><country xml:lang="fr">France</country><wicri:regionArea>Sanofi-Aventis Recherche, Cardiovascular-Thrombosis Research Department, 31036 Toulouse Cedex</wicri:regionArea></affiliation></author><author><name sortKey="Fariss, Robert" sort="Fariss, Robert" uniqKey="Fariss R" first="Robert" last="Fariss">Robert Fariss</name><affiliation wicri:level="2"><nlm:aff id="aff1">National Eye Institute, National Institutes of Health, Bethesda, MD 20892;</nlm:aff><country xml:lang="fr">États-Unis</country><placeName><region type="state">Maryland</region></placeName><wicri:cityArea>National Eye Institute, National Institutes of Health, Bethesda</wicri:cityArea></affiliation></author><author><name sortKey="Zhang, Yongqing" sort="Zhang, Yongqing" uniqKey="Zhang Y" first="Yongqing" last="Zhang">Yongqing Zhang</name><affiliation wicri:level="2"><nlm:aff id="aff9">TRIAD Technology Center, National Institute on Aging, National Institutes of Health, Baltimore, MD 21224;</nlm:aff><country xml:lang="fr">États-Unis</country><placeName><region type="state">Maryland</region></placeName><wicri:cityArea>TRIAD Technology Center, National Institute on Aging, National Institutes of Health, Baltimore</wicri:cityArea></affiliation></author><author><name sortKey="Wawrousek, Eric" sort="Wawrousek, Eric" uniqKey="Wawrousek E" first="Eric" last="Wawrousek">Eric Wawrousek</name><affiliation wicri:level="2"><nlm:aff id="aff1">National Eye Institute, National Institutes of Health, Bethesda, MD 20892;</nlm:aff><country xml:lang="fr">États-Unis</country><placeName><region type="state">Maryland</region></placeName><wicri:cityArea>National Eye Institute, National Institutes of Health, Bethesda</wicri:cityArea></affiliation></author><author><name sortKey="Tansey, Ginger" sort="Tansey, Ginger" uniqKey="Tansey G" first="Ginger" last="Tansey">Ginger Tansey</name><affiliation wicri:level="2"><nlm:aff id="aff1">National Eye Institute, National Institutes of Health, Bethesda, MD 20892;</nlm:aff><country xml:lang="fr">États-Unis</country><placeName><region type="state">Maryland</region></placeName><wicri:cityArea>National Eye Institute, National Institutes of Health, Bethesda</wicri:cityArea></affiliation></author><author><name sortKey="Raber, James" sort="Raber, James" uniqKey="Raber J" first="James" last="Raber">James Raber</name><affiliation wicri:level="2"><nlm:aff id="aff1">National Eye Institute, National Institutes of Health, Bethesda, MD 20892;</nlm:aff><country xml:lang="fr">États-Unis</country><placeName><region type="state">Maryland</region></placeName><wicri:cityArea>National Eye Institute, National Institutes of Health, Bethesda</wicri:cityArea></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 wicri:level="2"><nlm:aff id="aff10">Center for Vascular Biology, University of Connecticut, Farmington, CT 06030;</nlm:aff><country xml:lang="fr">États-Unis</country><placeName><region type="state">Connecticut</region></placeName><wicri:cityArea>Center for Vascular Biology, University of Connecticut, Farmington</wicri:cityArea></affiliation></author><author><name sortKey="Ding, Hao" sort="Ding, Hao" uniqKey="Ding H" first="Hao" last="Ding">Hao Ding</name><affiliation wicri:level="1"><nlm:aff id="aff11">Department of Biochemistry and Medical Genetics, University of Manitoba, Winnipeg, Canada MB R3E 3P5;</nlm:aff><country>Canada</country><wicri:regionArea>Department of Biochemistry and Medical Genetics, University of Manitoba, Winnipeg</wicri:regionArea></affiliation></author><author><name sortKey="Greenberg, David A" sort="Greenberg, David A" uniqKey="Greenberg D" first="David A." last="Greenberg">David A. Greenberg</name><affiliation wicri:level="2"><nlm:aff wicri:cut="; and" id="aff12">Buck Institute for Age Research, Novato, CA 94945</nlm:aff><country xml:lang="fr">États-Unis</country><placeName><region type="state">Californie</region></placeName><wicri:cityArea>Buck Institute for Age Research, Novato</wicri:cityArea></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 wicri:level="2"><nlm:aff id="aff9">TRIAD Technology Center, National Institute on Aging, National Institutes of Health, Baltimore, MD 21224;</nlm:aff><country xml:lang="fr">États-Unis</country><placeName><region type="state">Maryland</region></placeName><wicri:cityArea>TRIAD Technology Center, National Institute on Aging, National Institutes of Health, Baltimore</wicri:cityArea></affiliation></author><author><name sortKey="Herbert, Jean Marc" sort="Herbert, Jean Marc" uniqKey="Herbert J" first="Jean-Marc" last="Herbert">Jean-Marc Herbert</name><affiliation wicri:level="1"><nlm:aff id="aff8">Sanofi-Aventis Recherche, Cardiovascular-Thrombosis Research Department, 31036 Toulouse Cedex, France;</nlm:aff><country xml:lang="fr">France</country><wicri:regionArea>Sanofi-Aventis Recherche, Cardiovascular-Thrombosis Research Department, 31036 Toulouse Cedex</wicri:regionArea></affiliation></author><author><name sortKey="Nash, Andrew" sort="Nash, Andrew" uniqKey="Nash A" first="Andrew" last="Nash">Andrew Nash</name><affiliation wicri:level="1"><nlm:aff id="aff4">CSL Limited, Parkville, Victoria 3052, Australia;</nlm:aff><country xml:lang="fr">Australie</country><wicri:regionArea>CSL Limited, Parkville, Victoria 3052</wicri:regionArea></affiliation></author><author><name sortKey="Yla Herttuala, Seppo" sort="Yla Herttuala, Seppo" uniqKey="Yla Herttuala S" first="Seppo" last="Yla-Herttuala">Seppo Yla-Herttuala</name><affiliation wicri:level="1"><nlm:aff id="aff5">Department of Biotechnology and Molecular Medicine, University of Kuopio, FIN-70211, Kuopio, Finland;</nlm:aff><country xml:lang="fr">Finlande</country><wicri:regionArea>Department of Biotechnology and Molecular Medicine, University of Kuopio, FIN-70211, Kuopio</wicri:regionArea></affiliation></author><author><name sortKey="Cao, Yihai" sort="Cao, Yihai" uniqKey="Cao Y" first="Yihai" last="Cao">Yihai Cao</name><affiliation wicri:level="1"><nlm:aff id="aff13">Department of Microbiology, Karolinska Institute, 171 77 Stockholm, Sweden</nlm:aff><country xml:lang="fr">Suède</country><wicri:regionArea>Department of Microbiology, Karolinska Institute, 171 77 Stockholm</wicri:regionArea></affiliation></author><author><name sortKey="Watts, Ryan J" sort="Watts, Ryan J" uniqKey="Watts R" first="Ryan J." last="Watts">Ryan J. Watts</name><affiliation wicri:level="2"><nlm:aff id="aff3">Neurodegeneration Labs, Protein Chemistry, Genentech, Inc. San Francisco, CA 94080;</nlm:aff><country xml:lang="fr">États-Unis</country><placeName><region type="state">Californie</region></placeName><wicri:cityArea>Neurodegeneration Labs, Protein Chemistry, Genentech, Inc. San Francisco</wicri:cityArea></affiliation></author><author><name sortKey="Li, Xuri" sort="Li, Xuri" uniqKey="Li X" first="Xuri" last="Li">Xuri Li</name><affiliation wicri:level="2"><nlm:aff id="aff1">National Eye Institute, National Institutes of Health, Bethesda, MD 20892;</nlm:aff><country xml:lang="fr">États-Unis</country><placeName><region type="state">Maryland</region></placeName><wicri:cityArea>National Eye Institute, National Institutes of Health, Bethesda</wicri:cityArea></affiliation></author></analytic><series><title level="j">Proceedings of the National Academy of Sciences of the United States of America</title><idno type="ISSN">0027-8424</idno><idno type="eISSN">1091-6490</idno><imprint><date when="2009">2009</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en"><p>VEGF-B, a homolog of VEGF discovered a long time ago, has not been considered an important target in antiangiogenic therapy. Instead, it has received little attention from the field. In this study, using different animal models and multiple types of vascular cells, we revealed that although VEGF-B is dispensable for blood vessel growth, it is critical for their survival. Importantly, the survival effect of VEGF-B is not only on vascular endothelial cells, but also on pericytes, smooth muscle cells, and vascular stem/progenitor cells. In vivo, VEGF-B targeting inhibited both choroidal and retinal neovascularization. Mechanistically, we found that the vascular survival effect of VEGF-B is achieved by regulating the expression of many vascular prosurvival genes via both NP-1 and VEGFR-1. Our work thus indicates that the function of VEGF-B in the vascular system is to act as a “survival,” rather than an “angiogenic” factor and that VEGF-B inhibition may offer new therapeutic opportunities to treat neovascular 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">Proc Natl Acad Sci U S A</journal-id><journal-id journal-id-type="hwp">pnas</journal-id><journal-id journal-id-type="pmc">pnas</journal-id><journal-id journal-id-type="publisher-id">PNAS</journal-id><journal-title-group><journal-title>Proceedings of the National Academy of Sciences of the United States of America</journal-title></journal-title-group><issn pub-type="ppub">0027-8424</issn><issn pub-type="epub">1091-6490</issn><publisher><publisher-name>National Academy of Sciences</publisher-name></publisher></journal-meta><article-meta><article-id pub-id-type="pmid">19369214</article-id><article-id pub-id-type="pmc">2669337</article-id><article-id pub-id-type="publisher-id">7578</article-id><article-id pub-id-type="doi">10.1073/pnas.0813061106</article-id><article-categories><subj-group subj-group-type="heading"><subject>Biological Sciences</subject><subj-group><subject>Cell Biology</subject></subj-group></subj-group></article-categories><title-group><article-title>VEGF-B is dispensable for blood vessel growth but critical for their survival, and VEGF-B targeting inhibits pathological angiogenesis</article-title></title-group><contrib-group><contrib contrib-type="author"><name><surname>Zhang</surname><given-names>Fan</given-names></name><xref ref-type="aff" rid="aff1"><sup>a</sup></xref></contrib><contrib contrib-type="author"><name><surname>Tang</surname><given-names>Zhongshu</given-names></name><xref ref-type="aff" rid="aff1"><sup>a</sup></xref></contrib><contrib contrib-type="author"><name><surname>Hou</surname><given-names>Xu</given-names></name><xref ref-type="aff" rid="aff1"><sup>a</sup></xref></contrib><contrib contrib-type="author"><name><surname>Lennartsson</surname><given-names>Johan</given-names></name><xref ref-type="aff" rid="aff2"><sup>b</sup></xref></contrib><contrib contrib-type="author"><name><surname>Li</surname><given-names>Yang</given-names></name><xref ref-type="aff" rid="aff1"><sup>a</sup></xref></contrib><contrib contrib-type="author"><name><surname>Koch</surname><given-names>Alexander W.</given-names></name><xref ref-type="aff" rid="aff3"><sup>c</sup></xref></contrib><contrib contrib-type="author"><name><surname>Scotney</surname><given-names>Pierre</given-names></name><xref ref-type="aff" rid="aff4"><sup>d</sup></xref></contrib><contrib contrib-type="author"><name><surname>Lee</surname><given-names>Chunsik</given-names></name><xref ref-type="aff" rid="aff1"><sup>a</sup></xref></contrib><contrib contrib-type="author"><name><surname>Arjunan</surname><given-names>Pachiappan</given-names></name><xref ref-type="aff" rid="aff1"><sup>a</sup></xref></contrib><contrib contrib-type="author"><name><surname>Dong</surname><given-names>Lijin</given-names></name><xref ref-type="aff" rid="aff1"><sup>a</sup></xref></contrib><contrib contrib-type="author"><name><surname>Kumar</surname><given-names>Anil</given-names></name><xref ref-type="aff" rid="aff1"><sup>a</sup></xref></contrib><contrib contrib-type="author"><name><surname>Rissanen</surname><given-names>Tuomas T.</given-names></name><xref ref-type="aff" rid="aff5"><sup>e</sup></xref></contrib><contrib contrib-type="author"><name><surname>Wang</surname><given-names>Bin</given-names></name><xref ref-type="aff" rid="aff6"><sup>f</sup></xref></contrib><contrib contrib-type="author"><name><surname>Nagai</surname><given-names>Nobuo</given-names></name><xref ref-type="aff" rid="aff7"><sup>g</sup></xref></contrib><contrib contrib-type="author"><name><surname>Fons</surname><given-names>Pierre</given-names></name><xref ref-type="aff" rid="aff8"><sup>h</sup></xref></contrib><contrib contrib-type="author"><name><surname>Fariss</surname><given-names>Robert</given-names></name><xref ref-type="aff" rid="aff1"><sup>a</sup></xref></contrib><contrib contrib-type="author"><name><surname>Zhang</surname><given-names>Yongqing</given-names></name><xref ref-type="aff" rid="aff9"><sup>i</sup></xref></contrib><contrib contrib-type="author"><name><surname>Wawrousek</surname><given-names>Eric</given-names></name><xref ref-type="aff" rid="aff1"><sup>a</sup></xref></contrib><contrib contrib-type="author"><name><surname>Tansey</surname><given-names>Ginger</given-names></name><xref ref-type="aff" rid="aff1"><sup>a</sup></xref></contrib><contrib contrib-type="author"><name><surname>Raber</surname><given-names>James</given-names></name><xref ref-type="aff" rid="aff1"><sup>a</sup></xref></contrib><contrib contrib-type="author"><name><surname>Fong</surname><given-names>Guo-Hua</given-names></name><xref ref-type="aff" rid="aff10"><sup>j</sup></xref></contrib><contrib contrib-type="author"><name><surname>Ding</surname><given-names>Hao</given-names></name><xref ref-type="aff" rid="aff11"><sup>k</sup></xref></contrib><contrib contrib-type="author"><name><surname>Greenberg</surname><given-names>David A.</given-names></name><xref ref-type="aff" rid="aff12"><sup>l</sup></xref></contrib><contrib contrib-type="author"><name><surname>Becker</surname><given-names>Kevin G.</given-names></name><xref ref-type="aff" rid="aff9"><sup>i</sup></xref></contrib><contrib contrib-type="author"><name><surname>Herbert</surname><given-names>Jean-Marc</given-names></name><xref ref-type="aff" rid="aff8"><sup>h</sup></xref></contrib><contrib contrib-type="author"><name><surname>Nash</surname><given-names>Andrew</given-names></name><xref ref-type="aff" rid="aff4"><sup>d</sup></xref></contrib><contrib contrib-type="author"><name><surname>Yla-Herttuala</surname><given-names>Seppo</given-names></name><xref ref-type="aff" rid="aff5"><sup>e</sup></xref></contrib><contrib contrib-type="author"><name><surname>Cao</surname><given-names>Yihai</given-names></name><xref ref-type="aff" rid="aff13"><sup>m</sup></xref></contrib><contrib contrib-type="author"><name><surname>Watts</surname><given-names>Ryan J.</given-names></name><xref ref-type="aff" rid="aff3"><sup>c</sup></xref></contrib><contrib contrib-type="author"><name><surname>Li</surname><given-names>Xuri</given-names></name><xref ref-type="aff" rid="aff1"><sup>a</sup></xref><xref ref-type="corresp" rid="cor1"><sup>1</sup></xref></contrib><aff id="aff1"><sup>a</sup>National Eye Institute, National Institutes of Health, Bethesda, MD 20892;</aff><aff id="aff2"><sup>b</sup>Ludwig Institute for Cancer Research, Uppsala University, SE-751 24 Uppsala, Sweden;</aff><aff id="aff3"><sup>c</sup>Neurodegeneration Labs, Protein Chemistry, Genentech, Inc. San Francisco, CA 94080;</aff><aff id="aff4"><sup>d</sup>CSL Limited, Parkville, Victoria 3052, Australia;</aff><aff id="aff5"><sup>e</sup>Department of Biotechnology and Molecular Medicine, University of Kuopio, FIN-70211, Kuopio, Finland;</aff><aff id="aff6"><sup>f</sup>Department of Radiology, Medical Imaging Centre of the Affiliated Hospital, Weifang Medical University, Weifang 261042, China;</aff><aff id="aff7"><sup>g</sup>Department of Physiology, Kinki University School of Medicine, Osaka 589-8511, Japan;</aff><aff id="aff8"><sup>h</sup>Sanofi-Aventis Recherche, Cardiovascular-Thrombosis Research Department, 31036 Toulouse Cedex, France;</aff><aff id="aff9"><sup>i</sup>TRIAD Technology Center, National Institute on Aging, National Institutes of Health, Baltimore, MD 21224;</aff><aff id="aff10"><sup>j</sup>Center for Vascular Biology, University of Connecticut, Farmington, CT 06030;</aff><aff id="aff11"><sup>k</sup>Department of Biochemistry and Medical Genetics, University of Manitoba, Winnipeg, Canada MB R3E 3P5;</aff><aff id="aff12"><sup>l</sup>Buck Institute for Age Research, Novato, CA 94945; and</aff><aff id="aff13"><sup>m</sup>Department of Microbiology, Karolinska Institute, 171 77 Stockholm, Sweden</aff></contrib-group><author-notes><corresp id="cor1"><sup>1</sup>To whom correspondence should be addressed. E-mail: <email>lixur@nei.nih.gov</email></corresp><fn fn-type="edited-by"><p>Edited by Robert Langer, Massachusetts Institute of Technology, Cambridge, MA, and approved February 27, 2009</p></fn><fn fn-type="con"><p>Author contributions: X.L. designed research; F.Z., Z.T., X.H., J.L., Y.L., A.W.K., P.S., C.L., P.A., L.D., A.K., T.T.R., B.W., N.N., P.F., R.F., Y.Z., E.W., G.T., J.R., G.-H.F., H.D., D.A.G., K.G.B., J.-M.H., A.N., S.Y.-H., Y.C., and R.J.W. performed research; F.Z. and X.L. analyzed data; and F.Z. and X.L. wrote the paper.</p></fn></author-notes><pub-date pub-type="ppub"><day>14</day><month>4</month><year>2009</year></pub-date><pub-date pub-type="epub"><day>6</day><month>4</month><year>2009</year></pub-date><volume>106</volume><issue>15</issue><fpage>6152</fpage><lpage>6157</lpage><history><date date-type="received"><day>29</day><month>12</month><year>2008</year></date></history><permissions></permissions><self-uri xlink:title="pdf" xlink:type="simple" xlink:href="zpq01509006152.pdf"></self-uri><abstract><p>VEGF-B, a homolog of VEGF discovered a long time ago, has not been considered an important target in antiangiogenic therapy. Instead, it has received little attention from the field. In this study, using different animal models and multiple types of vascular cells, we revealed that although VEGF-B is dispensable for blood vessel growth, it is critical for their survival. Importantly, the survival effect of VEGF-B is not only on vascular endothelial cells, but also on pericytes, smooth muscle cells, and vascular stem/progenitor cells. In vivo, VEGF-B targeting inhibited both choroidal and retinal neovascularization. Mechanistically, we found that the vascular survival effect of VEGF-B is achieved by regulating the expression of many vascular prosurvival genes via both NP-1 and VEGFR-1. Our work thus indicates that the function of VEGF-B in the vascular system is to act as a “survival,” rather than an “angiogenic” factor and that VEGF-B inhibition may offer new therapeutic opportunities to treat neovascular diseases.</p></abstract><kwd-group><kwd>apoptosis</kwd><kwd>vascular survival</kwd><kwd>ocular neovascularization</kwd></kwd-group></article-meta></front></pmc></record>Pour manipuler ce document sous Unix (Dilib)
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