Angiopoietin-4 increases permeability of blood vessels and promotes lymphatic dilation
Identifieur interne : 001512 ( Pmc/Checkpoint ); précédent : 001511; suivant : 001513Angiopoietin-4 increases permeability of blood vessels and promotes lymphatic dilation
Auteurs : Cristina T. Kesler ; Ethel R. Pereira ; Cheryl H. Cui ; Gregory M. Nelson ; David J. Masuck ; James W. Baish ; Timothy P. PaderaSource :
- The FASEB Journal [ 0892-6638 ] ; 2015.
Abstract
The angiopoietin (Ang) ligands are potential therapeutic targets for lymphatic related diseases, which include lymphedema and cancer. Ang-1 and Ang-2 functions are established, but those of Ang-4 are poorly understood. We used intravital fluorescence microscopy to characterize Ang-4 actions on T241 murine fibrosarcoma-associated vessels in mice. The diameters of lymphatic vessels draining Ang-4- or VEGF-C (positive control)-expressing tumors increased to 123 and 135 μm, respectively, and parental, mock-transduced (negative controls) and tumors expressing Ang-1 or Ang-2 remained at baseline (∼60 μm). Ang-4 decreased human dermal lymphatic endothelial cell (LEC) monolayer permeability by 27% while increasing human dermal blood endothelial cell (BEC) monolayer permeability by 200%.
Url:
DOI: 10.1096/fj.14-268920
PubMed: 25977256
PubMed Central: 4550378
Affiliations:
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<author><name sortKey="Kesler, Cristina T" sort="Kesler, Cristina T" uniqKey="Kesler C" first="Cristina T." last="Kesler">Cristina T. Kesler</name>
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<author><name sortKey="Pereira, Ethel R" sort="Pereira, Ethel R" uniqKey="Pereira E" first="Ethel R." last="Pereira">Ethel R. Pereira</name>
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<author><name sortKey="Cui, Cheryl H" sort="Cui, Cheryl H" uniqKey="Cui C" first="Cheryl H." last="Cui">Cheryl H. Cui</name>
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<author><name sortKey="Nelson, Gregory M" sort="Nelson, Gregory M" uniqKey="Nelson G" first="Gregory M." last="Nelson">Gregory M. Nelson</name>
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<author><name sortKey="Masuck, David J" sort="Masuck, David J" uniqKey="Masuck D" first="David J." last="Masuck">David J. Masuck</name>
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<author><name sortKey="Baish, James W" sort="Baish, James W" uniqKey="Baish J" first="James W." last="Baish">James W. Baish</name>
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<author><name sortKey="Padera, Timothy P" sort="Padera, Timothy P" uniqKey="Padera T" first="Timothy P." last="Padera">Timothy P. Padera</name>
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<front><div type="abstract" xml:lang="en"><p>The angiopoietin (Ang) ligands are potential therapeutic targets for lymphatic related diseases, which include lymphedema and cancer. Ang-1 and Ang-2 functions are established, but those of Ang-4 are poorly understood. We used intravital fluorescence microscopy to characterize Ang-4 actions on T241 murine fibrosarcoma-associated vessels in mice. The diameters of lymphatic vessels draining Ang-4- or VEGF-C (positive control)-expressing tumors increased to 123 and 135 μm, respectively, and parental, mock-transduced (negative controls) and tumors expressing Ang-1 or Ang-2 remained at baseline (∼60 μm). Ang-4 decreased human dermal lymphatic endothelial cell (LEC) monolayer permeability by 27% while increasing human dermal blood endothelial cell (BEC) monolayer permeability by 200%. <italic>In vivo</italic>
, Ang-4 stimulated a 4.5-fold increase in tumor-associated blood vessel permeability compared with control when measured using intravital quantitative multiphoton microscopy. Ang-4 activated receptor signaling in both LECs and BECs, evidenced by tyrosine kinase with Ig and endothelial growth factor homology domains-2 (TIE2) receptor, protein kinase B, and Erk1,2 phosphorylation detectable by immunoblotting. These data suggest that Ang-4 actions are mediated through cell-type-specific networks and that lymphatic vessel dilation occurs secondarily to increased vascular leakage. Ang-4 also promoted survival of LECs. Thus, blocking Ang-4 may prune the draining lymphatic vasculature and decrease interstitial fluid pressure (IFP) by reducing vascular permeability.—Kesler, C. T., Pereira, E. R., Cui, C. H., Nelson, G. M., Masuck, D. J., Baish, J. W., Padera, T. P. Angiopoietin-4 increases permeability of blood vessels and promotes lymphatic dilation.</p>
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<front><journal-meta><journal-id journal-id-type="nlm-ta">FASEB J</journal-id>
<journal-id journal-id-type="iso-abbrev">FASEB J</journal-id>
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<article-categories><subj-group subj-group-type="heading"><subject>Research Communication</subject>
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<title-group><article-title>Angiopoietin-4 increases permeability of blood vessels and promotes lymphatic dilation</article-title>
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<contrib-group><contrib contrib-type="author"><name><surname>Kesler</surname>
<given-names>Cristina T.</given-names>
</name>
<xref ref-type="aff" rid="aff1">*</xref>
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<contrib contrib-type="author"><name><surname>Pereira</surname>
<given-names>Ethel R.</given-names>
</name>
<xref ref-type="aff" rid="aff1">*</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Cui</surname>
<given-names>Cheryl H.</given-names>
</name>
<xref ref-type="aff" rid="aff1">*</xref>
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<contrib contrib-type="author"><name><surname>Nelson</surname>
<given-names>Gregory M.</given-names>
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<xref ref-type="aff" rid="aff2"><sup>†</sup>
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<contrib contrib-type="author"><name><surname>Masuck</surname>
<given-names>David J.</given-names>
</name>
<xref ref-type="aff" rid="aff1">*</xref>
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<contrib contrib-type="author"><name><surname>Baish</surname>
<given-names>James W.</given-names>
</name>
<xref ref-type="aff" rid="aff3"><sup>‡</sup>
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<contrib contrib-type="author"><name><surname>Padera</surname>
<given-names>Timothy P.</given-names>
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<xref ref-type="aff" rid="aff1">*</xref>
<xref ref-type="corresp" rid="cor1"><sup>1</sup>
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<aff><target id="aff1" target-type="aff">*</target>
Edwin Steele Laboratory for Tumor Biology, Department of Radiation Oncology, Massachusetts General Hospital, Boston, Massachusetts, USA;<target id="aff2" target-type="aff"><sup>†</sup>
</target>
Harold B. Lee Library, Brigham Young University, Provo, Utah, USA; and<target id="aff3" target-type="aff"><sup>‡</sup>
</target>
Department of Biomedical Engineering, Bucknell University, Lewisburg, Pennsylvania, USA</aff>
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<author-notes><corresp id="cor1"><label>1</label>
Correspondence: <addr-line>Massachusetts General Hospital, Department of Radiation Oncology, Cox-7, 100 Blossom St., Boston, MA 02114, USA</addr-line>
. E-mail: <email>tpadera@steele.mgh.harvard.edu</email>
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<pub-date pub-type="ppub"><month>9</month>
<year>2015</year>
</pub-date>
<pub-date pub-type="epub"><day>14</day>
<month>5</month>
<year>2015</year>
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<pub-date pub-type="pmc-release"><day>1</day>
<month>9</month>
<year>2016</year>
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<volume>29</volume>
<issue>9</issue>
<fpage>3668</fpage>
<lpage>3677</lpage>
<history><date date-type="received"><day>18</day>
<month>12</month>
<year>2014</year>
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<date date-type="accepted"><day>4</day>
<month>5</month>
<year>2015</year>
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<permissions><copyright-statement>© FASEB</copyright-statement>
<copyright-year>2015</copyright-year>
<copyright-holder>FASEB</copyright-holder>
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<self-uri xlink:title="pdf" xlink:href="fasebj268920.pdf"></self-uri>
<abstract><p>The angiopoietin (Ang) ligands are potential therapeutic targets for lymphatic related diseases, which include lymphedema and cancer. Ang-1 and Ang-2 functions are established, but those of Ang-4 are poorly understood. We used intravital fluorescence microscopy to characterize Ang-4 actions on T241 murine fibrosarcoma-associated vessels in mice. The diameters of lymphatic vessels draining Ang-4- or VEGF-C (positive control)-expressing tumors increased to 123 and 135 μm, respectively, and parental, mock-transduced (negative controls) and tumors expressing Ang-1 or Ang-2 remained at baseline (∼60 μm). Ang-4 decreased human dermal lymphatic endothelial cell (LEC) monolayer permeability by 27% while increasing human dermal blood endothelial cell (BEC) monolayer permeability by 200%. <italic>In vivo</italic>
, Ang-4 stimulated a 4.5-fold increase in tumor-associated blood vessel permeability compared with control when measured using intravital quantitative multiphoton microscopy. Ang-4 activated receptor signaling in both LECs and BECs, evidenced by tyrosine kinase with Ig and endothelial growth factor homology domains-2 (TIE2) receptor, protein kinase B, and Erk1,2 phosphorylation detectable by immunoblotting. These data suggest that Ang-4 actions are mediated through cell-type-specific networks and that lymphatic vessel dilation occurs secondarily to increased vascular leakage. Ang-4 also promoted survival of LECs. Thus, blocking Ang-4 may prune the draining lymphatic vasculature and decrease interstitial fluid pressure (IFP) by reducing vascular permeability.—Kesler, C. T., Pereira, E. R., Cui, C. H., Nelson, G. M., Masuck, D. J., Baish, J. W., Padera, T. P. Angiopoietin-4 increases permeability of blood vessels and promotes lymphatic dilation.</p>
</abstract>
<kwd-group><kwd>endothelial</kwd>
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<tree><noCountry><name sortKey="Baish, James W" sort="Baish, James W" uniqKey="Baish J" first="James W." last="Baish">James W. Baish</name>
<name sortKey="Cui, Cheryl H" sort="Cui, Cheryl H" uniqKey="Cui C" first="Cheryl H." last="Cui">Cheryl H. Cui</name>
<name sortKey="Kesler, Cristina T" sort="Kesler, Cristina T" uniqKey="Kesler C" first="Cristina T." last="Kesler">Cristina T. Kesler</name>
<name sortKey="Masuck, David J" sort="Masuck, David J" uniqKey="Masuck D" first="David J." last="Masuck">David J. Masuck</name>
<name sortKey="Nelson, Gregory M" sort="Nelson, Gregory M" uniqKey="Nelson G" first="Gregory M." last="Nelson">Gregory M. Nelson</name>
<name sortKey="Padera, Timothy P" sort="Padera, Timothy P" uniqKey="Padera T" first="Timothy P." last="Padera">Timothy P. Padera</name>
<name sortKey="Pereira, Ethel R" sort="Pereira, Ethel R" uniqKey="Pereira E" first="Ethel R." last="Pereira">Ethel R. Pereira</name>
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