VEGFR-3 controls tip to stalk conversion at vessel fusion sites by reinforcing Notch signalling
Identifieur interne : 002980 ( Pmc/Corpus ); précédent : 002979; suivant : 002981VEGFR-3 controls tip to stalk conversion at vessel fusion sites by reinforcing Notch signalling
Auteurs : Tuomas Tammela ; Georgia Zarkada ; Harri Nurmi ; Lars Jakobsson ; Krista Heinolainen ; Denis Tvorogov ; Wei Zheng ; Claudio A. Franco ; Aino Murtom Ki ; Evelyn Aranda ; Naoyuki Miura ; Seppo Yl Herttuala ; Marcus Fruttiger ; Taija M Kinen ; Anne Eichmann ; Jeffrey W. Pollard ; Holger Gerhardt ; Kari AlitaloSource :
- Nature Cell Biology [ 1465-7392 ] ; 2011.
Abstract
Angiogenesis, the growth of new blood vessels, involves specification of endothelial cells to tip cells and stalk cells, which is controlled by Notch signalling, whereas vascular endothelial growth factor receptor (VEGFR)-2 and VEGFR-3 have been implicated in angiogenic sprouting. Surprisingly, we found that endothelial deletion of
Url:
DOI: 10.1038/ncb2331
PubMed: 21909098
PubMed Central: 3261765
Links to Exploration step
PMC:3261765Le document en format XML
<record><TEI><teiHeader><fileDesc><titleStmt><title xml:lang="en">VEGFR-3 controls tip to stalk conversion at vessel fusion sites by reinforcing Notch signalling</title><author><name sortKey="Tammela, Tuomas" sort="Tammela, Tuomas" uniqKey="Tammela T" first="Tuomas" last="Tammela">Tuomas Tammela</name><affiliation><nlm:aff id="A1">Molecular/Cancer Biology Laboratory, Institute for Molecular Medicine Finland, Research Programs Unit and Department of Pathology, Haartman Institute, Biomedicum Helsinki, PO Box 63 (Haartmaninkatu 8), 00014 University of Helsinki, Finland</nlm:aff></affiliation></author><author><name sortKey="Zarkada, Georgia" sort="Zarkada, Georgia" uniqKey="Zarkada G" first="Georgia" last="Zarkada">Georgia Zarkada</name><affiliation><nlm:aff id="A1">Molecular/Cancer Biology Laboratory, Institute for Molecular Medicine Finland, Research Programs Unit and Department of Pathology, Haartman Institute, Biomedicum Helsinki, PO Box 63 (Haartmaninkatu 8), 00014 University of Helsinki, Finland</nlm:aff></affiliation></author><author><name sortKey="Nurmi, Harri" sort="Nurmi, Harri" uniqKey="Nurmi H" first="Harri" last="Nurmi">Harri Nurmi</name><affiliation><nlm:aff id="A1">Molecular/Cancer Biology Laboratory, Institute for Molecular Medicine Finland, Research Programs Unit and Department of Pathology, Haartman Institute, Biomedicum Helsinki, PO Box 63 (Haartmaninkatu 8), 00014 University of Helsinki, Finland</nlm:aff></affiliation></author><author><name sortKey="Jakobsson, Lars" sort="Jakobsson, Lars" uniqKey="Jakobsson L" first="Lars" last="Jakobsson">Lars Jakobsson</name><affiliation><nlm:aff id="A2">Vascular Biology Laboratory, London Research Institute—Cancer Research UK, 44 Lincoln’s Inn Fields, London WC2A 3PX, UK</nlm:aff></affiliation></author><author><name sortKey="Heinolainen, Krista" sort="Heinolainen, Krista" uniqKey="Heinolainen K" first="Krista" last="Heinolainen">Krista Heinolainen</name><affiliation><nlm:aff id="A1">Molecular/Cancer Biology Laboratory, Institute for Molecular Medicine Finland, Research Programs Unit and Department of Pathology, Haartman Institute, Biomedicum Helsinki, PO Box 63 (Haartmaninkatu 8), 00014 University of Helsinki, Finland</nlm:aff></affiliation></author><author><name sortKey="Tvorogov, Denis" sort="Tvorogov, Denis" uniqKey="Tvorogov D" first="Denis" last="Tvorogov">Denis Tvorogov</name><affiliation><nlm:aff id="A1">Molecular/Cancer Biology Laboratory, Institute for Molecular Medicine Finland, Research Programs Unit and Department of Pathology, Haartman Institute, Biomedicum Helsinki, PO Box 63 (Haartmaninkatu 8), 00014 University of Helsinki, Finland</nlm:aff></affiliation></author><author><name sortKey="Zheng, Wei" sort="Zheng, Wei" uniqKey="Zheng W" first="Wei" last="Zheng">Wei Zheng</name><affiliation><nlm:aff id="A1">Molecular/Cancer Biology Laboratory, Institute for Molecular Medicine Finland, Research Programs Unit and Department of Pathology, Haartman Institute, Biomedicum Helsinki, PO Box 63 (Haartmaninkatu 8), 00014 University of Helsinki, Finland</nlm:aff></affiliation></author><author><name sortKey="Franco, Claudio A" sort="Franco, Claudio A" uniqKey="Franco C" first="Claudio A." last="Franco">Claudio A. Franco</name><affiliation><nlm:aff id="A2">Vascular Biology Laboratory, London Research Institute—Cancer Research UK, 44 Lincoln’s Inn Fields, London WC2A 3PX, UK</nlm:aff></affiliation></author><author><name sortKey="Murtom Ki, Aino" sort="Murtom Ki, Aino" uniqKey="Murtom Ki A" first="Aino" last="Murtom Ki">Aino Murtom Ki</name><affiliation><nlm:aff id="A1">Molecular/Cancer Biology Laboratory, Institute for Molecular Medicine Finland, Research Programs Unit and Department of Pathology, Haartman Institute, Biomedicum Helsinki, PO Box 63 (Haartmaninkatu 8), 00014 University of Helsinki, Finland</nlm:aff></affiliation></author><author><name sortKey="Aranda, Evelyn" sort="Aranda, Evelyn" uniqKey="Aranda E" first="Evelyn" last="Aranda">Evelyn Aranda</name><affiliation><nlm:aff id="A3">Department of Developmental and Molecular Biology, Albert Einstein College of Medicine, New York, New York 10461, USA</nlm:aff></affiliation></author><author><name sortKey="Miura, Naoyuki" sort="Miura, Naoyuki" uniqKey="Miura N" first="Naoyuki" last="Miura">Naoyuki Miura</name><affiliation><nlm:aff id="A4">Department of Biochemistry, Hamamatsu University School of Medicine, 431-3192 Hamamatsu, Japan</nlm:aff></affiliation></author><author><name sortKey="Yl Herttuala, Seppo" sort="Yl Herttuala, Seppo" uniqKey="Yl Herttuala S" first="Seppo" last="Yl Herttuala">Seppo Yl Herttuala</name><affiliation><nlm:aff id="A5">A. I. Virtanen Institute and Department of Medicine, University of Kuopio, PO Box 1627, 70211 Kuopio, Finland</nlm:aff></affiliation></author><author><name sortKey="Fruttiger, Marcus" sort="Fruttiger, Marcus" uniqKey="Fruttiger M" first="Marcus" last="Fruttiger">Marcus Fruttiger</name><affiliation><nlm:aff id="A6">Institute of Ophthalmology, University College London, London EC1V 9EL, UK</nlm:aff></affiliation></author><author><name sortKey="M Kinen, Taija" sort="M Kinen, Taija" uniqKey="M Kinen T" first="Taija" last="M Kinen">Taija M Kinen</name><affiliation><nlm:aff id="A1">Molecular/Cancer Biology Laboratory, Institute for Molecular Medicine Finland, Research Programs Unit and Department of Pathology, Haartman Institute, Biomedicum Helsinki, PO Box 63 (Haartmaninkatu 8), 00014 University of Helsinki, Finland</nlm:aff></affiliation></author><author><name sortKey="Eichmann, Anne" sort="Eichmann, Anne" uniqKey="Eichmann A" first="Anne" last="Eichmann">Anne Eichmann</name><affiliation><nlm:aff id="A7">Institut National de la Santé et de la Recherche Médicale U833, Collège de France, 11 Place Marcelin Berthelot, 75005 Paris, France</nlm:aff></affiliation></author><author><name sortKey="Pollard, Jeffrey W" sort="Pollard, Jeffrey W" uniqKey="Pollard J" first="Jeffrey W." last="Pollard">Jeffrey W. Pollard</name><affiliation><nlm:aff id="A3">Department of Developmental and Molecular Biology, Albert Einstein College of Medicine, New York, New York 10461, USA</nlm:aff></affiliation></author><author><name sortKey="Gerhardt, Holger" sort="Gerhardt, Holger" uniqKey="Gerhardt H" first="Holger" last="Gerhardt">Holger Gerhardt</name><affiliation><nlm:aff id="A2">Vascular Biology Laboratory, London Research Institute—Cancer Research UK, 44 Lincoln’s Inn Fields, London WC2A 3PX, UK</nlm:aff></affiliation><affiliation><nlm:aff id="A8">Vascular Patterning Laboratory, Vesalius Research Center, VIB, Campus Gasthuisberg, B-3000 Leuven, Belgium</nlm:aff></affiliation></author><author><name sortKey="Alitalo, Kari" sort="Alitalo, Kari" uniqKey="Alitalo K" first="Kari" last="Alitalo">Kari Alitalo</name><affiliation><nlm:aff id="A1">Molecular/Cancer Biology Laboratory, Institute for Molecular Medicine Finland, Research Programs Unit and Department of Pathology, Haartman Institute, Biomedicum Helsinki, PO Box 63 (Haartmaninkatu 8), 00014 University of Helsinki, Finland</nlm:aff></affiliation></author></titleStmt><publicationStmt><idno type="wicri:source">PMC</idno><idno type="pmid">21909098</idno><idno type="pmc">3261765</idno><idno type="url">http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3261765</idno><idno type="RBID">PMC:3261765</idno><idno type="doi">10.1038/ncb2331</idno><date when="2011">2011</date><idno type="wicri:Area/Pmc/Corpus">002980</idno><idno type="wicri:explorRef" wicri:stream="Pmc" wicri:step="Corpus" wicri:corpus="PMC">002980</idno></publicationStmt><sourceDesc><biblStruct><analytic><title xml:lang="en" level="a" type="main">VEGFR-3 controls tip to stalk conversion at vessel fusion sites by reinforcing Notch signalling</title><author><name sortKey="Tammela, Tuomas" sort="Tammela, Tuomas" uniqKey="Tammela T" first="Tuomas" last="Tammela">Tuomas Tammela</name><affiliation><nlm:aff id="A1">Molecular/Cancer Biology Laboratory, Institute for Molecular Medicine Finland, Research Programs Unit and Department of Pathology, Haartman Institute, Biomedicum Helsinki, PO Box 63 (Haartmaninkatu 8), 00014 University of Helsinki, Finland</nlm:aff></affiliation></author><author><name sortKey="Zarkada, Georgia" sort="Zarkada, Georgia" uniqKey="Zarkada G" first="Georgia" last="Zarkada">Georgia Zarkada</name><affiliation><nlm:aff id="A1">Molecular/Cancer Biology Laboratory, Institute for Molecular Medicine Finland, Research Programs Unit and Department of Pathology, Haartman Institute, Biomedicum Helsinki, PO Box 63 (Haartmaninkatu 8), 00014 University of Helsinki, Finland</nlm:aff></affiliation></author><author><name sortKey="Nurmi, Harri" sort="Nurmi, Harri" uniqKey="Nurmi H" first="Harri" last="Nurmi">Harri Nurmi</name><affiliation><nlm:aff id="A1">Molecular/Cancer Biology Laboratory, Institute for Molecular Medicine Finland, Research Programs Unit and Department of Pathology, Haartman Institute, Biomedicum Helsinki, PO Box 63 (Haartmaninkatu 8), 00014 University of Helsinki, Finland</nlm:aff></affiliation></author><author><name sortKey="Jakobsson, Lars" sort="Jakobsson, Lars" uniqKey="Jakobsson L" first="Lars" last="Jakobsson">Lars Jakobsson</name><affiliation><nlm:aff id="A2">Vascular Biology Laboratory, London Research Institute—Cancer Research UK, 44 Lincoln’s Inn Fields, London WC2A 3PX, UK</nlm:aff></affiliation></author><author><name sortKey="Heinolainen, Krista" sort="Heinolainen, Krista" uniqKey="Heinolainen K" first="Krista" last="Heinolainen">Krista Heinolainen</name><affiliation><nlm:aff id="A1">Molecular/Cancer Biology Laboratory, Institute for Molecular Medicine Finland, Research Programs Unit and Department of Pathology, Haartman Institute, Biomedicum Helsinki, PO Box 63 (Haartmaninkatu 8), 00014 University of Helsinki, Finland</nlm:aff></affiliation></author><author><name sortKey="Tvorogov, Denis" sort="Tvorogov, Denis" uniqKey="Tvorogov D" first="Denis" last="Tvorogov">Denis Tvorogov</name><affiliation><nlm:aff id="A1">Molecular/Cancer Biology Laboratory, Institute for Molecular Medicine Finland, Research Programs Unit and Department of Pathology, Haartman Institute, Biomedicum Helsinki, PO Box 63 (Haartmaninkatu 8), 00014 University of Helsinki, Finland</nlm:aff></affiliation></author><author><name sortKey="Zheng, Wei" sort="Zheng, Wei" uniqKey="Zheng W" first="Wei" last="Zheng">Wei Zheng</name><affiliation><nlm:aff id="A1">Molecular/Cancer Biology Laboratory, Institute for Molecular Medicine Finland, Research Programs Unit and Department of Pathology, Haartman Institute, Biomedicum Helsinki, PO Box 63 (Haartmaninkatu 8), 00014 University of Helsinki, Finland</nlm:aff></affiliation></author><author><name sortKey="Franco, Claudio A" sort="Franco, Claudio A" uniqKey="Franco C" first="Claudio A." last="Franco">Claudio A. Franco</name><affiliation><nlm:aff id="A2">Vascular Biology Laboratory, London Research Institute—Cancer Research UK, 44 Lincoln’s Inn Fields, London WC2A 3PX, UK</nlm:aff></affiliation></author><author><name sortKey="Murtom Ki, Aino" sort="Murtom Ki, Aino" uniqKey="Murtom Ki A" first="Aino" last="Murtom Ki">Aino Murtom Ki</name><affiliation><nlm:aff id="A1">Molecular/Cancer Biology Laboratory, Institute for Molecular Medicine Finland, Research Programs Unit and Department of Pathology, Haartman Institute, Biomedicum Helsinki, PO Box 63 (Haartmaninkatu 8), 00014 University of Helsinki, Finland</nlm:aff></affiliation></author><author><name sortKey="Aranda, Evelyn" sort="Aranda, Evelyn" uniqKey="Aranda E" first="Evelyn" last="Aranda">Evelyn Aranda</name><affiliation><nlm:aff id="A3">Department of Developmental and Molecular Biology, Albert Einstein College of Medicine, New York, New York 10461, USA</nlm:aff></affiliation></author><author><name sortKey="Miura, Naoyuki" sort="Miura, Naoyuki" uniqKey="Miura N" first="Naoyuki" last="Miura">Naoyuki Miura</name><affiliation><nlm:aff id="A4">Department of Biochemistry, Hamamatsu University School of Medicine, 431-3192 Hamamatsu, Japan</nlm:aff></affiliation></author><author><name sortKey="Yl Herttuala, Seppo" sort="Yl Herttuala, Seppo" uniqKey="Yl Herttuala S" first="Seppo" last="Yl Herttuala">Seppo Yl Herttuala</name><affiliation><nlm:aff id="A5">A. I. Virtanen Institute and Department of Medicine, University of Kuopio, PO Box 1627, 70211 Kuopio, Finland</nlm:aff></affiliation></author><author><name sortKey="Fruttiger, Marcus" sort="Fruttiger, Marcus" uniqKey="Fruttiger M" first="Marcus" last="Fruttiger">Marcus Fruttiger</name><affiliation><nlm:aff id="A6">Institute of Ophthalmology, University College London, London EC1V 9EL, UK</nlm:aff></affiliation></author><author><name sortKey="M Kinen, Taija" sort="M Kinen, Taija" uniqKey="M Kinen T" first="Taija" last="M Kinen">Taija M Kinen</name><affiliation><nlm:aff id="A1">Molecular/Cancer Biology Laboratory, Institute for Molecular Medicine Finland, Research Programs Unit and Department of Pathology, Haartman Institute, Biomedicum Helsinki, PO Box 63 (Haartmaninkatu 8), 00014 University of Helsinki, Finland</nlm:aff></affiliation></author><author><name sortKey="Eichmann, Anne" sort="Eichmann, Anne" uniqKey="Eichmann A" first="Anne" last="Eichmann">Anne Eichmann</name><affiliation><nlm:aff id="A7">Institut National de la Santé et de la Recherche Médicale U833, Collège de France, 11 Place Marcelin Berthelot, 75005 Paris, France</nlm:aff></affiliation></author><author><name sortKey="Pollard, Jeffrey W" sort="Pollard, Jeffrey W" uniqKey="Pollard J" first="Jeffrey W." last="Pollard">Jeffrey W. Pollard</name><affiliation><nlm:aff id="A3">Department of Developmental and Molecular Biology, Albert Einstein College of Medicine, New York, New York 10461, USA</nlm:aff></affiliation></author><author><name sortKey="Gerhardt, Holger" sort="Gerhardt, Holger" uniqKey="Gerhardt H" first="Holger" last="Gerhardt">Holger Gerhardt</name><affiliation><nlm:aff id="A2">Vascular Biology Laboratory, London Research Institute—Cancer Research UK, 44 Lincoln’s Inn Fields, London WC2A 3PX, UK</nlm:aff></affiliation><affiliation><nlm:aff id="A8">Vascular Patterning Laboratory, Vesalius Research Center, VIB, Campus Gasthuisberg, B-3000 Leuven, Belgium</nlm:aff></affiliation></author><author><name sortKey="Alitalo, Kari" sort="Alitalo, Kari" uniqKey="Alitalo K" first="Kari" last="Alitalo">Kari Alitalo</name><affiliation><nlm:aff id="A1">Molecular/Cancer Biology Laboratory, Institute for Molecular Medicine Finland, Research Programs Unit and Department of Pathology, Haartman Institute, Biomedicum Helsinki, PO Box 63 (Haartmaninkatu 8), 00014 University of Helsinki, Finland</nlm:aff></affiliation></author></analytic><series><title level="j">Nature Cell Biology</title><idno type="ISSN">1465-7392</idno><idno type="eISSN">1476-4679</idno><imprint><date when="2011">2011</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en"><p id="P1">Angiogenesis, the growth of new blood vessels, involves specification of endothelial cells to tip cells and stalk cells, which is controlled by Notch signalling, whereas vascular endothelial growth factor receptor (VEGFR)-2 and VEGFR-3 have been implicated in angiogenic sprouting. Surprisingly, we found that endothelial deletion of <italic>Vegfr3</italic>, but not VEGFR-3-blocking antibodies, postnatally led to excessive angiogenic sprouting and branching, and decreased the level of Notch signalling, indicating that VEGFR-3 possesses passive and active signalling modalities. Furthermore, macrophages expressing the VEGFR-3 and VEGFR-2 ligand VEGF-C localized to vessel branch points, and <italic>Vegfc</italic> heterozygous mice exhibited inefficient angiogenesis characterized by decreased vascular branching. FoxC2 is a known regulator of Notch ligand and target gene expression, and <italic>Foxc2</italic><sup>+/−</sup>; <italic>Vegfr3</italic><sup>+/−</sup> compound heterozygosity recapitulated homozygous loss of <italic>Vegfr3</italic>. These results indicate that macrophage-derived VEGF-C activates VEGFR-3 in tip cells to reinforce Notch signalling, which contributes to the phenotypic conversion of endothelial cells at fusion points of vessel sprouts.</p></div></front></TEI><pmc article-type="research-article" xml:lang="en"><pmc-comment>The publisher of this article does not allow downloading of the full text in XML form.</pmc-comment>
<pmc-dir>properties manuscript</pmc-dir>
<front><journal-meta><journal-id journal-id-type="nlm-journal-id">100890575</journal-id><journal-id journal-id-type="pubmed-jr-id">21417</journal-id><journal-id journal-id-type="nlm-ta">Nat Cell Biol</journal-id><journal-title-group><journal-title>Nature Cell Biology</journal-title></journal-title-group><issn pub-type="ppub">1465-7392</issn><issn pub-type="epub">1476-4679</issn></journal-meta><article-meta><article-id pub-id-type="pmid">21909098</article-id><article-id pub-id-type="pmc">3261765</article-id><article-id pub-id-type="doi">10.1038/ncb2331</article-id><article-id pub-id-type="manuscript">NIHMS341220</article-id><article-categories><subj-group subj-group-type="heading"><subject>Article</subject></subj-group></article-categories><title-group><article-title>VEGFR-3 controls tip to stalk conversion at vessel fusion sites by reinforcing Notch signalling</article-title></title-group><contrib-group><contrib contrib-type="author"><name><surname>Tammela</surname><given-names>Tuomas</given-names></name><xref rid="A1" ref-type="aff">1</xref><xref rid="FN2" ref-type="author-notes">9</xref></contrib><contrib contrib-type="author"><name><surname>Zarkada</surname><given-names>Georgia</given-names></name><xref rid="A1" ref-type="aff">1</xref><xref rid="FN2" ref-type="author-notes">9</xref></contrib><contrib contrib-type="author"><name><surname>Nurmi</surname><given-names>Harri</given-names></name><xref rid="A1" ref-type="aff">1</xref></contrib><contrib contrib-type="author"><name><surname>Jakobsson</surname><given-names>Lars</given-names></name><xref rid="A2" ref-type="aff">2</xref><xref rid="FN3" ref-type="author-notes">10</xref></contrib><contrib contrib-type="author"><name><surname>Heinolainen</surname><given-names>Krista</given-names></name><xref rid="A1" ref-type="aff">1</xref></contrib><contrib contrib-type="author"><name><surname>Tvorogov</surname><given-names>Denis</given-names></name><xref rid="A1" ref-type="aff">1</xref></contrib><contrib contrib-type="author"><name><surname>Zheng</surname><given-names>Wei</given-names></name><xref rid="A1" ref-type="aff">1</xref></contrib><contrib contrib-type="author"><name><surname>Franco</surname><given-names>Claudio A.</given-names></name><xref rid="A2" ref-type="aff">2</xref></contrib><contrib contrib-type="author"><name><surname>Murtomäki</surname><given-names>Aino</given-names></name><xref rid="A1" ref-type="aff">1</xref></contrib><contrib contrib-type="author"><name><surname>Aranda</surname><given-names>Evelyn</given-names></name><xref rid="A3" ref-type="aff">3</xref></contrib><contrib contrib-type="author"><name><surname>Miura</surname><given-names>Naoyuki</given-names></name><xref rid="A4" ref-type="aff">4</xref></contrib><contrib contrib-type="author"><name><surname>Ylä-Herttuala</surname><given-names>Seppo</given-names></name><xref rid="A5" ref-type="aff">5</xref></contrib><contrib contrib-type="author"><name><surname>Fruttiger</surname><given-names>Marcus</given-names></name><xref rid="A6" ref-type="aff">6</xref></contrib><contrib contrib-type="author"><name><surname>Mäkinen</surname><given-names>Taija</given-names></name><xref rid="A1" ref-type="aff">1</xref><xref rid="FN3" ref-type="author-notes">10</xref></contrib><contrib contrib-type="author"><name><surname>Eichmann</surname><given-names>Anne</given-names></name><xref rid="A7" ref-type="aff">7</xref></contrib><contrib contrib-type="author"><name><surname>Pollard</surname><given-names>Jeffrey W.</given-names></name><xref rid="A3" ref-type="aff">3</xref></contrib><contrib contrib-type="author"><name><surname>Gerhardt</surname><given-names>Holger</given-names></name><xref rid="A2" ref-type="aff">2</xref><xref rid="A8" ref-type="aff">8</xref></contrib><contrib contrib-type="author"><name><surname>Alitalo</surname><given-names>Kari</given-names></name><xref rid="A1" ref-type="aff">1</xref><xref rid="FN1" ref-type="author-notes">11</xref></contrib></contrib-group><aff id="A1"><label>1</label>Molecular/Cancer Biology Laboratory, Institute for Molecular Medicine Finland, Research Programs Unit and Department of Pathology, Haartman Institute, Biomedicum Helsinki, PO Box 63 (Haartmaninkatu 8), 00014 University of Helsinki, Finland</aff><aff id="A2"><label>2</label>Vascular Biology Laboratory, London Research Institute—Cancer Research UK, 44 Lincoln’s Inn Fields, London WC2A 3PX, UK</aff><aff id="A3"><label>3</label>Department of Developmental and Molecular Biology, Albert Einstein College of Medicine, New York, New York 10461, USA</aff><aff id="A4"><label>4</label>Department of Biochemistry, Hamamatsu University School of Medicine, 431-3192 Hamamatsu, Japan</aff><aff id="A5"><label>5</label>A. I. Virtanen Institute and Department of Medicine, University of Kuopio, PO Box 1627, 70211 Kuopio, Finland</aff><aff id="A6"><label>6</label>Institute of Ophthalmology, University College London, London EC1V 9EL, UK</aff><aff id="A7"><label>7</label>Institut National de la Santé et de la Recherche Médicale U833, Collège de France, 11 Place Marcelin Berthelot, 75005 Paris, France</aff><aff id="A8"><label>8</label>Vascular Patterning Laboratory, Vesalius Research Center, VIB, Campus Gasthuisberg, B-3000 Leuven, Belgium</aff><author-notes><corresp id="FN1"><label>11</label>Correspondence should be addressed to K.A. (<email>Kari.Alitalo@Helsinki.Fi</email>)</corresp><fn id="FN2" fn-type="equal"><label>9</label><p>These authors contributed equally to this work.</p></fn><fn id="FN3" fn-type="present-address"><label>10</label><p>Present addresses: Vascular Biology, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Scheeles Väg 2, SE171 77 Stockholm, Sweden (L.K.); Lymphatic Development Laboratory, Cancer Research UK London Research Institute, 44 Lincoln’s Inn Fields, London WC2A 3PX, UK (T.M.).</p></fn></author-notes><pub-date pub-type="nihms-submitted"><day>15</day><month>12</month><year>2011</year></pub-date><pub-date pub-type="epub"><day>11</day><month>9</month><year>2011</year></pub-date><pub-date pub-type="pmc-release"><day>19</day><month>1</month><year>2012</year></pub-date><volume>13</volume><issue>10</issue><fpage>1202</fpage><lpage>1213</lpage><permissions><copyright-statement>© 2011 Macmillan Publishers Limited. All rights reserved.</copyright-statement><copyright-year>2011</copyright-year></permissions><abstract><p id="P1">Angiogenesis, the growth of new blood vessels, involves specification of endothelial cells to tip cells and stalk cells, which is controlled by Notch signalling, whereas vascular endothelial growth factor receptor (VEGFR)-2 and VEGFR-3 have been implicated in angiogenic sprouting. Surprisingly, we found that endothelial deletion of <italic>Vegfr3</italic>, but not VEGFR-3-blocking antibodies, postnatally led to excessive angiogenic sprouting and branching, and decreased the level of Notch signalling, indicating that VEGFR-3 possesses passive and active signalling modalities. Furthermore, macrophages expressing the VEGFR-3 and VEGFR-2 ligand VEGF-C localized to vessel branch points, and <italic>Vegfc</italic> heterozygous mice exhibited inefficient angiogenesis characterized by decreased vascular branching. FoxC2 is a known regulator of Notch ligand and target gene expression, and <italic>Foxc2</italic><sup>+/−</sup>; <italic>Vegfr3</italic><sup>+/−</sup> compound heterozygosity recapitulated homozygous loss of <italic>Vegfr3</italic>. These results indicate that macrophage-derived VEGF-C activates VEGFR-3 in tip cells to reinforce Notch signalling, which contributes to the phenotypic conversion of endothelial cells at fusion points of vessel sprouts.</p></abstract><funding-group><award-group><funding-source country="United States">National Cancer Institute : NCI</funding-source><award-id>R01 CA131270-05 || CA</award-id></award-group></funding-group></article-meta></front></pmc></record>Pour manipuler ce document sous Unix (Dilib)
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