Adiponectin‐Mediated Modulation of Lymphatic Vessel Formation and Lymphedema
Identifieur interne : 002523 ( Pmc/Checkpoint ); précédent : 002522; suivant : 002524Adiponectin‐Mediated Modulation of Lymphatic Vessel Formation and Lymphedema
Auteurs : Yuuki Shimizu ; Rei Shibata ; Masakazu Ishii ; Koji Ohashi ; Takahiro Kambara ; Yusuke Uemura ; Daisuke Yuasa ; Yoshiyuki Kataoka ; Shinji Kihara ; Toyoaki Murohara ; Noriyuki OuchiSource :
- Journal of the American Heart Association: Cardiovascular and Cerebrovascular Disease [ 2047-9980 ] ; 2013.
Abstract
Obesity is linked with an increased risk of lymphedema, which is a serious clinical problem. Adiponectin is a circulating adipokine that is down‐regulated in obese states. We investigated the effects of adiponectin on lymphatic vessel formation in a model of lymphedema and dissected its mechanisms.
A mouse model of lymphedema was created via ablation of tail surface lymphatic network. Adiponectin‐knockout mice showed the greater diameter of the injured tail compared with wild‐type mice, which was associated with lower numbers of lymphatic endothelial cells (LECs). Systemic delivery of adiponectin reduced the thickness of the injured tail and enhanced LEC formation in wild‐type and adiponectin‐knockout mice. Adiponectin administration also improved the edema of injured tails in obese KKAy mice. Treatment with adiponectin protein stimulated the differentiation of human LECs into tubelike structures and increased LEC viability. Adiponectin treatment promoted the phosphorylation of AMP‐activated protein kinase (AMPK), Akt, and endothelial nitric oxide synthase n LECs. Blockade of AMPK or Akt activity abolished adiponectin‐stimulated increase in LEC differentiation and viability and endothelial nitric oxide synthase phosphorylation. Inhibition of AMPK activation also suppressed adiponectin‐induced Akt phosphorylation in LECs. In contrast, inactivation of Akt signaling had no effects on adiponectin‐mediated AMPK phosphorylation in LECs. Furthermore, adiponectin administration did not affect the thickening of the damaged tail in endothelial nitric oxide synthase–knockout mice.
Adiponectin can promote lymphatic vessel formation via activation of AMPK/Akt/endothelial nitric oxide synthase signaling within LECs, thereby leading to amelioration of lymphedema.
Url:
DOI: 10.1161/JAHA.113.000438
PubMed: 24052499
PubMed Central: 3835259
Affiliations:
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<record><TEI><teiHeader><fileDesc><titleStmt><title xml:lang="en">Adiponectin‐Mediated Modulation of Lymphatic Vessel Formation and Lymphedema</title><author><name sortKey="Shimizu, Yuuki" sort="Shimizu, Yuuki" uniqKey="Shimizu Y" first="Yuuki" last="Shimizu">Yuuki Shimizu</name><affiliation><nlm:aff>NONE</nlm:aff></affiliation></author><author><name sortKey="Shibata, Rei" sort="Shibata, Rei" uniqKey="Shibata R" first="Rei" last="Shibata">Rei Shibata</name><affiliation><nlm:aff>NONE</nlm:aff></affiliation></author><author><name sortKey="Ishii, Masakazu" sort="Ishii, Masakazu" uniqKey="Ishii M" first="Masakazu" last="Ishii">Masakazu Ishii</name><affiliation><nlm:aff>NONE</nlm:aff></affiliation></author><author><name sortKey="Ohashi, Koji" sort="Ohashi, Koji" uniqKey="Ohashi K" first="Koji" last="Ohashi">Koji Ohashi</name><affiliation><nlm:aff>NONE</nlm:aff></affiliation></author><author><name sortKey="Kambara, Takahiro" sort="Kambara, Takahiro" uniqKey="Kambara T" first="Takahiro" last="Kambara">Takahiro Kambara</name><affiliation><nlm:aff>NONE</nlm:aff></affiliation></author><author><name sortKey="Uemura, Yusuke" sort="Uemura, Yusuke" uniqKey="Uemura Y" first="Yusuke" last="Uemura">Yusuke Uemura</name><affiliation><nlm:aff>NONE</nlm:aff></affiliation></author><author><name sortKey="Yuasa, Daisuke" sort="Yuasa, Daisuke" uniqKey="Yuasa D" first="Daisuke" last="Yuasa">Daisuke Yuasa</name><affiliation><nlm:aff>NONE</nlm:aff></affiliation></author><author><name sortKey="Kataoka, Yoshiyuki" sort="Kataoka, Yoshiyuki" uniqKey="Kataoka Y" first="Yoshiyuki" last="Kataoka">Yoshiyuki Kataoka</name><affiliation><nlm:aff>NONE</nlm:aff></affiliation></author><author><name sortKey="Kihara, Shinji" sort="Kihara, Shinji" uniqKey="Kihara S" first="Shinji" last="Kihara">Shinji Kihara</name><affiliation><nlm:aff>NONE</nlm:aff></affiliation></author><author><name sortKey="Murohara, Toyoaki" sort="Murohara, Toyoaki" uniqKey="Murohara T" first="Toyoaki" last="Murohara">Toyoaki Murohara</name><affiliation><nlm:aff>NONE</nlm:aff></affiliation></author><author><name sortKey="Ouchi, Noriyuki" sort="Ouchi, Noriyuki" uniqKey="Ouchi N" first="Noriyuki" last="Ouchi">Noriyuki Ouchi</name><affiliation><nlm:aff>NONE</nlm:aff></affiliation></author></titleStmt><publicationStmt><idno type="wicri:source">PMC</idno><idno type="pmid">24052499</idno><idno type="pmc">3835259</idno><idno type="url">http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3835259</idno><idno type="RBID">PMC:3835259</idno><idno type="doi">10.1161/JAHA.113.000438</idno><date when="2013">2013</date><idno type="wicri:Area/Pmc/Corpus">004019</idno><idno type="wicri:explorRef" wicri:stream="Pmc" wicri:step="Corpus" wicri:corpus="PMC">004019</idno><idno type="wicri:Area/Pmc/Curation">004018</idno><idno type="wicri:explorRef" wicri:stream="Pmc" wicri:step="Curation">004018</idno><idno type="wicri:Area/Pmc/Checkpoint">002523</idno><idno type="wicri:explorRef" wicri:stream="Pmc" wicri:step="Checkpoint">002523</idno></publicationStmt><sourceDesc><biblStruct><analytic><title xml:lang="en" level="a" type="main">Adiponectin‐Mediated Modulation of Lymphatic Vessel Formation and Lymphedema</title><author><name sortKey="Shimizu, Yuuki" sort="Shimizu, Yuuki" uniqKey="Shimizu Y" first="Yuuki" last="Shimizu">Yuuki Shimizu</name><affiliation><nlm:aff>NONE</nlm:aff></affiliation></author><author><name sortKey="Shibata, Rei" sort="Shibata, Rei" uniqKey="Shibata R" first="Rei" last="Shibata">Rei Shibata</name><affiliation><nlm:aff>NONE</nlm:aff></affiliation></author><author><name sortKey="Ishii, Masakazu" sort="Ishii, Masakazu" uniqKey="Ishii M" first="Masakazu" last="Ishii">Masakazu Ishii</name><affiliation><nlm:aff>NONE</nlm:aff></affiliation></author><author><name sortKey="Ohashi, Koji" sort="Ohashi, Koji" uniqKey="Ohashi K" first="Koji" last="Ohashi">Koji Ohashi</name><affiliation><nlm:aff>NONE</nlm:aff></affiliation></author><author><name sortKey="Kambara, Takahiro" sort="Kambara, Takahiro" uniqKey="Kambara T" first="Takahiro" last="Kambara">Takahiro Kambara</name><affiliation><nlm:aff>NONE</nlm:aff></affiliation></author><author><name sortKey="Uemura, Yusuke" sort="Uemura, Yusuke" uniqKey="Uemura Y" first="Yusuke" last="Uemura">Yusuke Uemura</name><affiliation><nlm:aff>NONE</nlm:aff></affiliation></author><author><name sortKey="Yuasa, Daisuke" sort="Yuasa, Daisuke" uniqKey="Yuasa D" first="Daisuke" last="Yuasa">Daisuke Yuasa</name><affiliation><nlm:aff>NONE</nlm:aff></affiliation></author><author><name sortKey="Kataoka, Yoshiyuki" sort="Kataoka, Yoshiyuki" uniqKey="Kataoka Y" first="Yoshiyuki" last="Kataoka">Yoshiyuki Kataoka</name><affiliation><nlm:aff>NONE</nlm:aff></affiliation></author><author><name sortKey="Kihara, Shinji" sort="Kihara, Shinji" uniqKey="Kihara S" first="Shinji" last="Kihara">Shinji Kihara</name><affiliation><nlm:aff>NONE</nlm:aff></affiliation></author><author><name sortKey="Murohara, Toyoaki" sort="Murohara, Toyoaki" uniqKey="Murohara T" first="Toyoaki" last="Murohara">Toyoaki Murohara</name><affiliation><nlm:aff>NONE</nlm:aff></affiliation></author><author><name sortKey="Ouchi, Noriyuki" sort="Ouchi, Noriyuki" uniqKey="Ouchi N" first="Noriyuki" last="Ouchi">Noriyuki Ouchi</name><affiliation><nlm:aff>NONE</nlm:aff></affiliation></author></analytic><series><title level="j">Journal of the American Heart Association: Cardiovascular and Cerebrovascular Disease</title><idno type="eISSN">2047-9980</idno><imprint><date when="2013">2013</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en"><sec><title>Background</title><p>Obesity is linked with an increased risk of lymphedema, which is a serious clinical problem. Adiponectin is a circulating adipokine that is down‐regulated in obese states. We investigated the effects of adiponectin on lymphatic vessel formation in a model of lymphedema and dissected its mechanisms.</p></sec><sec><title>Methods and Results</title><p>A mouse model of lymphedema was created via ablation of tail surface lymphatic network. Adiponectin‐knockout mice showed the greater diameter of the injured tail compared with wild‐type mice, which was associated with lower numbers of lymphatic endothelial cells (LECs). Systemic delivery of adiponectin reduced the thickness of the injured tail and enhanced LEC formation in wild‐type and adiponectin‐knockout mice. Adiponectin administration also improved the edema of injured tails in obese KKAy mice. Treatment with adiponectin protein stimulated the differentiation of human LECs into tubelike structures and increased LEC viability. Adiponectin treatment promoted the phosphorylation of AMP‐activated protein kinase (AMPK), Akt, and endothelial nitric oxide synthase n LECs. Blockade of AMPK or Akt activity abolished adiponectin‐stimulated increase in LEC differentiation and viability and endothelial nitric oxide synthase phosphorylation. Inhibition of AMPK activation also suppressed adiponectin‐induced Akt phosphorylation in LECs. In contrast, inactivation of Akt signaling had no effects on adiponectin‐mediated AMPK phosphorylation in LECs. Furthermore, adiponectin administration did not affect the thickening of the damaged tail in endothelial nitric oxide synthase–knockout mice.</p></sec><sec><title>Conclusions</title><p>Adiponectin can promote lymphatic vessel formation via activation of AMPK/Akt/endothelial nitric oxide synthase signaling within LECs, thereby leading to amelioration of lymphedema.</p></sec></div></front><back><div1 type="bibliography"><listBibl><biblStruct><analytic><author><name sortKey="Shaw, C" uniqKey="Shaw C">C Shaw</name></author><author><name sortKey="Mortimer, P" uniqKey="Mortimer P">P Mortimer</name></author><author><name sortKey="Judd, Pa" uniqKey="Judd P">PA Judd</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Meric, F" uniqKey="Meric F">F Meric</name></author><author><name sortKey="Buchholz, Ta" uniqKey="Buchholz T">TA Buchholz</name></author><author><name sortKey="Mirza, Nq" uniqKey="Mirza N">NQ Mirza</name></author><author><name sortKey="Vlastos, G" 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<front><journal-meta><journal-id journal-id-type="nlm-ta">J Am Heart Assoc</journal-id><journal-id journal-id-type="iso-abbrev">J Am Heart Assoc</journal-id><journal-id journal-id-type="hwp">ahaoa</journal-id><journal-id journal-id-type="publisher-id">jah3</journal-id><journal-title-group><journal-title>Journal of the American Heart Association: Cardiovascular and Cerebrovascular Disease</journal-title></journal-title-group><issn pub-type="epub">2047-9980</issn><publisher><publisher-name>Blackwell Publishing Ltd</publisher-name></publisher></journal-meta><article-meta><article-id pub-id-type="pmid">24052499</article-id><article-id pub-id-type="pmc">3835259</article-id><article-id pub-id-type="publisher-id">jah3303</article-id><article-id pub-id-type="doi">10.1161/JAHA.113.000438</article-id><article-categories><subj-group subj-group-type="heading"><subject>Original Research</subject><subj-group><subject>Vascular Medicine</subject></subj-group></subj-group></article-categories><title-group><article-title>Adiponectin‐Mediated Modulation of Lymphatic Vessel Formation and Lymphedema</article-title></title-group><contrib-group><contrib contrib-type="author"><name><surname>Shimizu</surname><given-names>Yuuki</given-names></name><degrees>MD, PhD</degrees><xref ref-type="aff" rid="au1"></xref></contrib><contrib contrib-type="author"><name><surname>Shibata</surname><given-names>Rei</given-names></name><degrees>MD, PhD</degrees><xref ref-type="aff" rid="au1"></xref></contrib><contrib contrib-type="author"><name><surname>Ishii</surname><given-names>Masakazu</given-names></name><degrees>PhD</degrees><xref ref-type="aff" rid="au1"></xref></contrib><contrib contrib-type="author"><name><surname>Ohashi</surname><given-names>Koji</given-names></name><degrees>MD, PhD</degrees><xref ref-type="aff" rid="au2"></xref></contrib><contrib contrib-type="author"><name><surname>Kambara</surname><given-names>Takahiro</given-names></name><degrees>MD</degrees><xref ref-type="aff" rid="au1"></xref></contrib><contrib contrib-type="author"><name><surname>Uemura</surname><given-names>Yusuke</given-names></name><degrees>MD</degrees><xref ref-type="aff" rid="au1"></xref></contrib><contrib contrib-type="author"><name><surname>Yuasa</surname><given-names>Daisuke</given-names></name><degrees>MD</degrees><xref ref-type="aff" rid="au1"></xref></contrib><contrib contrib-type="author"><name><surname>Kataoka</surname><given-names>Yoshiyuki</given-names></name><degrees>MD</degrees><xref ref-type="aff" rid="au1"></xref></contrib><contrib contrib-type="author"><name><surname>Kihara</surname><given-names>Shinji</given-names></name><degrees>MD, PhD</degrees><xref ref-type="aff" rid="au3"></xref></contrib><contrib contrib-type="author"><name><surname>Murohara</surname><given-names>Toyoaki</given-names></name><degrees>MD, PhD</degrees><xref ref-type="aff" rid="au1"></xref></contrib><contrib contrib-type="author"><name><surname>Ouchi</surname><given-names>Noriyuki</given-names></name><degrees>MD, PhD</degrees><xref ref-type="corresp" rid="cor1"></xref><xref ref-type="aff" rid="au2"></xref></contrib><aff id="au1"><label>1</label><institution>Department of Cardiology, Nagoya University Graduate School of Medicine,</institution><addr-line>Nagoya, Japan (Y.S., R.S., M.I., T.K., Y.U., D.Y., Y.K., T.M.)</addr-line></aff><aff id="au2"><label>2</label><institution>Department of Molecular Cardiology, Nagoya University Graduate School of Medicine,</institution><addr-line>Nagoya, Japan (K.O., N.O.)</addr-line></aff><aff id="au3"><label>3</label><institution>Department of Biomedical Informatics, Osaka University Graduate School of Medicine,</institution><addr-line>Nagoya, Japan (S.K.)</addr-line></aff></contrib-group><author-notes><corresp id="cor1"><bold>Correspondence to:</bold> Noriyuki Ouchi, MD, PhD or Rei Shibata, MD, PhD, Department of Molecular Cardiology, Nagoya University Graduate School of Medicine, 65 Tsurumai, Showa, Nagoya, 466‐8550, Japan. E‐mail: <email>nouchi@med.nagoya-u.ac.jp</email> or <email>rshibata@med.nagoya-u.ac.jp</email></corresp></author-notes><pub-date pub-type="collection"><month>10</month><year>2013</year></pub-date><pub-date pub-type="epub"><day>25</day><month>10</month><year>2013</year></pub-date><volume>2</volume><issue>5</issue><elocation-id>e000438</elocation-id><history><date date-type="received"><day>23</day><month>7</month><year>2013</year></date><date date-type="accepted"><day>14</day><month>8</month><year>2013</year></date></history><permissions><copyright-statement>© 2013 The Authors. Published on behalf of the American Heart Association, Inc., by Wiley Blackwell.
</copyright-statement><copyright-year>2013</copyright-year><license license-type="creative-commons"><license-p>This is an Open Access article under the terms of the <ext-link ext-link-type="uri" xlink:href="http://creativecommons.org/licenses/by-nc/3.0/">Creative Commons Attribution‐NonCommercial</ext-link> License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes.</license-p></license></permissions><abstract><sec><title>Background</title><p>Obesity is linked with an increased risk of lymphedema, which is a serious clinical problem. Adiponectin is a circulating adipokine that is down‐regulated in obese states. We investigated the effects of adiponectin on lymphatic vessel formation in a model of lymphedema and dissected its mechanisms.</p></sec><sec><title>Methods and Results</title><p>A mouse model of lymphedema was created via ablation of tail surface lymphatic network. Adiponectin‐knockout mice showed the greater diameter of the injured tail compared with wild‐type mice, which was associated with lower numbers of lymphatic endothelial cells (LECs). Systemic delivery of adiponectin reduced the thickness of the injured tail and enhanced LEC formation in wild‐type and adiponectin‐knockout mice. Adiponectin administration also improved the edema of injured tails in obese KKAy mice. Treatment with adiponectin protein stimulated the differentiation of human LECs into tubelike structures and increased LEC viability. Adiponectin treatment promoted the phosphorylation of AMP‐activated protein kinase (AMPK), Akt, and endothelial nitric oxide synthase n LECs. Blockade of AMPK or Akt activity abolished adiponectin‐stimulated increase in LEC differentiation and viability and endothelial nitric oxide synthase phosphorylation. Inhibition of AMPK activation also suppressed adiponectin‐induced Akt phosphorylation in LECs. In contrast, inactivation of Akt signaling had no effects on adiponectin‐mediated AMPK phosphorylation in LECs. Furthermore, adiponectin administration did not affect the thickening of the damaged tail in endothelial nitric oxide synthase–knockout mice.</p></sec><sec><title>Conclusions</title><p>Adiponectin can promote lymphatic vessel formation via activation of AMPK/Akt/endothelial nitric oxide synthase signaling within LECs, thereby leading to amelioration of lymphedema.</p></sec></abstract><kwd-group><kwd>adiponectin</kwd><kwd>Akt</kwd><kwd>AMPK</kwd><kwd>eNOS</kwd><kwd>lymphangiogenesis</kwd></kwd-group></article-meta></front></pmc><affiliations><list></list><tree><noCountry><name sortKey="Ishii, Masakazu" sort="Ishii, Masakazu" uniqKey="Ishii M" first="Masakazu" last="Ishii">Masakazu Ishii</name><name sortKey="Kambara, Takahiro" sort="Kambara, Takahiro" uniqKey="Kambara T" first="Takahiro" last="Kambara">Takahiro Kambara</name><name sortKey="Kataoka, Yoshiyuki" sort="Kataoka, Yoshiyuki" uniqKey="Kataoka Y" first="Yoshiyuki" last="Kataoka">Yoshiyuki Kataoka</name><name sortKey="Kihara, Shinji" sort="Kihara, Shinji" uniqKey="Kihara S" first="Shinji" last="Kihara">Shinji Kihara</name><name sortKey="Murohara, Toyoaki" sort="Murohara, Toyoaki" uniqKey="Murohara T" first="Toyoaki" last="Murohara">Toyoaki Murohara</name><name sortKey="Ohashi, Koji" sort="Ohashi, Koji" uniqKey="Ohashi K" first="Koji" last="Ohashi">Koji Ohashi</name><name sortKey="Ouchi, Noriyuki" sort="Ouchi, Noriyuki" uniqKey="Ouchi N" first="Noriyuki" last="Ouchi">Noriyuki Ouchi</name><name sortKey="Shibata, Rei" sort="Shibata, Rei" uniqKey="Shibata R" first="Rei" last="Shibata">Rei Shibata</name><name sortKey="Shimizu, Yuuki" sort="Shimizu, Yuuki" uniqKey="Shimizu Y" first="Yuuki" last="Shimizu">Yuuki Shimizu</name><name sortKey="Uemura, Yusuke" sort="Uemura, Yusuke" uniqKey="Uemura Y" first="Yusuke" last="Uemura">Yusuke Uemura</name><name sortKey="Yuasa, Daisuke" sort="Yuasa, Daisuke" uniqKey="Yuasa D" first="Daisuke" last="Yuasa">Daisuke Yuasa</name></noCountry></tree></affiliations></record>Pour manipuler ce document sous Unix (Dilib)
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