The molecular basis for impaired hypoxia-induced VEGF expression in diabetic tissues

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This results in part from a failure to form adequate compensatory microvasculature in response to ischemia. Since vascular endothelial growth factor (VEGF) is an essential mediator of neovascularization, we examined …"><meta name="twitter:image" content="https://cdn.ncbi.nlm.nih.gov/pubmed/persistent/pubmed-meta-image-v2.jpg">  <link rel="search" type="application/opensearchdescription+xml" href="https://cdn.ncbi.nlm.nih.gov/pubmed/persistent/opensearch.xml" title="PubMed search">  <noscript> <link rel="stylesheet" type="text/css" href="https://cdn.ncbi.nlm.nih.gov/pubmed/ed1a5a1f-b279-475e-88e3-75f261729818/core/no-script.css"> </noscript> <meta name="citation_title" content="The molecular basis for impaired hypoxia-induced VEGF expression in diabetic tissues"> <meta name="citation_authors" content="Thangarajah H;Yao D;Chang EI;Shi Y;Jazayeri L;Vial IN;Galiano RD;Du XL;Grogan R;Galvez MG;Januszyk M;Brownlee M;Gurtner GC;"> <meta name="citation_date" content="08/11/2009"> <meta name="citation_publisher" content="Proc Natl Acad Sci U S A"> <meta name="citation_journal_title" content="Proceedings of the National Academy of Sciences of the United States of America"> <meta name="citation_pmid" content="19666581"> <meta name="citation_abstract_html_url" content="https://pubmed.ncbi.nlm.nih.gov/19666581/"> <meta name="citation_volume" content="106"> <meta name="citation_issue" content="32"> <meta name="citation_doi" content="10.1073/pnas.0906670106"> <meta name="citation_issn" content="1091-6490"> <link rel="canonical" href="https://pubmed.ncbi.nlm.nih.gov/19666581/" /> </head> <body > <noscript> <div class="no-script-banner" id="no-script-banner"> <div class="warning-message"> <div class="warning-message-text"> This site needs JavaScript to work properly. 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new collection</label> </li> <li> <input type="radio" id="collections-action-panel-existing" class="collections-existing" name="collections" value="existing" checked="true" data-ga-category="save_share" data-ga-action="collections" data-ga-label="collections_radio_existing"> <label for="collections-action-panel-existing">Add to an existing collection</label> </li> </ul> </div> <div class="controls-wrapper"> <div class="action-panel-control-wrap new-collections-controls"> <label for="collections-action-panel-add-to-new" class="action-panel-label required-field-asterisk"> Name your collection: </label> <input type="text" name="add-to-new-collection" id="collections-action-panel-add-to-new" class="collections-action-add-to-new" pattern="[^"&=<>\/]*" title="The following characters are not allowed in the Name field: "&=<>/" maxlength="100" data-ga-category="save_share" data-ga-action="create_collection" data-ga-label="non_favorties_collection"> <div class="collections-new-name-too-long usa-input-error-message selection-validation-message"> Name must be less than 100 characters </div> </div> <div class="action-panel-control-wrap existing-collections-controls"> <label for="collections-action-panel-add-to-existing" class="action-panel-label"> Choose a collection: </label> <select id="collections-action-panel-add-to-existing" class="action-panel-selector collections-action-add-to-existing" data-ga-category="save_share" data-ga-action="select_collection" data-ga-label="($('#collections-action-add-to-existing').val() === 'Favorites') ? 'Favorites' : 'non_favorites_collection'"> </select> <div class="collections-retry-load-on-error usa-input-error-message selection-validation-message"> Unable to load your collection due to an error<br> <a href="#">Please try again</a> </div> </div> </div> <div class="action-panel-actions"> <button class="action-panel-submit" type="submit" data-loading-label="Adding..." data-pinger-ignore data-ga-category="save_share" data-ga-action="collections" data-ga-label="add"> Add </button> <button class="action-panel-cancel" aria-label="Close 'Add to Collections' panel" ref="linksrc=close_collections_panel" aria-controls="collections-action-panel" aria-expanded="false" data-ga-category="save_share" data-ga-action="collections" data-ga-label="cancel"> Cancel </button> </div> </form> </div> </div> <div id="bibliography-action-panel" class="bibliography-action-panel action-panel in-progress-dots-panel" aria-hidden="true" data-bibliography-open-panel-enabled="false" data-bibliography-open-panel-url-hash="#open-bibliography-panel"> <div class="inner-wrap"> <h3 class="action-panel-heading"> Add to My Bibliography </h3> <form id="bibliography-action-panel-form" class="bibliography-action-panel-form action-panel-content action-form action-panel-smaller-selectors" data-add-to-bibliography-max-amount="100" data-add-to-bibliography-batch-size="10" data-bibliography-delegates-url="/list-bibliography-delegates/" data-add-to-bibliography-url="/add-to-bibliography/" data-get-article-ids-by-search-url="/get-article-ids-by-search/" data-mybib-root-url="https://www.ncbi.nlm.nih.gov/myncbi/collections/mybibliography/"> <input type="hidden" name="csrfmiddlewaretoken" value="P3cOK6vkfrPgo1HD3GGyUV7O0P9JAFhuB8WKTx6fe5V6ngbUs43qBhuwt4zw1bIW"> <div class="action-panel-control-wrap bibliographies-controls"> <div class="choice-group"> <ul class="bibliographies-action-add radio-group-items"> <li> <input name="bibliography" id="my-bibliography" class="my-bibliography" type="radio" checked/> <label for="my-bibliography">My Bibliography</label> </li> </ul> </div> </div> <div class="bibliographies-retry-load-on-error usa-input-error-message selection-validation-message"> Unable to load your delegates due to an error<br> <a href="#">Please try again</a> </div> <div class="action-panel-actions"> <button class="action-panel-submit" type="submit" data-loading-label="Adding..." data-pinger-ignore> Add </button> <button class="action-panel-cancel" aria-label="Close 'Add to bibliography' panel" ref="linksrc=close_bibliography_panel" aria-controls="bibliography-action-panel" aria-expanded="false" data-ga-category="save_share" data-ga-action="mybib" data-ga-label="cancel"> Cancel </button> </div> </form> </div> </div> <div id="saved-search-action-panel" class="saved-search-action-panel action-panel " aria-hidden="true" data-saved-search-open-panel-enabled="false" data-saved-search-open-panel-url-hash="#open-saved-search-panel"> <div class="inner-wrap"> <h2 class="action-panel-heading"> Your saved search </h2> <form id="saved-search-action-panel-form" class="saved-search-action-panel-form action-panel-content action-form" data-create-saved-search-url="/create-saved-search/" data-try-search-terms-url="/try-search-term/" data-saved-search-root-url="https://www.ncbi.nlm.nih.gov/myncbi/searches/"> <input type="hidden" name="csrfmiddlewaretoken" value="P3cOK6vkfrPgo1HD3GGyUV7O0P9JAFhuB8WKTx6fe5V6ngbUs43qBhuwt4zw1bIW"> <div class="action-panel-control-wrap"> <label for="saved-search-name" class="action-panel-label saved-search-name-label required-field-asterisk"> Name of saved search: </label> <input maxlength="200" type="text" name="saved-search-name" id="saved-search-name" class="saved-search-name" value="" required pattern="[^"&=<>\/]*" title="The following characters are not allowed in the Name field: "&=<>/"> </div> <div class="action-panel-control-wrap"> <label for="saved-search-term" class="action-panel-label required-field-asterisk"> Search terms: </label> <textarea name="saved-search-term" id="saved-search-term" class="saved-search-term" required></textarea> </div> <div class="test-search-term-wrap"> <a href="#" class="try-search-term">Test search terms</a> </div> <div class="choice-group action-panel-extra-margin-top"> <span class="action-panel-label" id="fieldset-label"> Would you like email updates of new search results? </span> <fieldset id="saved-search-alert" aria-describedby="fieldset-label"> <legend class="usa-sr-only">Saved Search Alert Radio Buttons</legend> <ul class="radio-group-items"> <li> <input type="radio" id="saved-search-alert-yes" class="saved-search-alert-yes" name="saved-search-alert" value="yes" checked> <label for="saved-search-alert-yes" class="action-panel-label">Yes</label> </li> <li> <input aria-label="No radio input" type="radio" id="saved-search-alert-no" class="saved-search-alert-no" name="saved-search-alert" value="no"> <label for="saved-search-alert-no" class="action-panel-label">No</label> </li> </ul> </fieldset> </div> <div class="alert-schedule-wrap"> <div class="action-panel-control-wrap"> <label class="action-panel-label"> Email: </label> <span aria-label="Email address" id="saved-search-email" class="action-panel-label"><span class="action-panel-label-bold"></span> (<a class="myncbi-account-settings" href="https://www.ncbi.nlm.nih.gov/account/settings/">change</a>)</span> </div> <div class="action-panel-control-wrap action-panel-extra-margin-top"> <label for="saved-search-frequency" class="action-panel-label"> Frequency: </label> <select id="saved-search-frequency" class="no-border-panel-selector saved-search-frequency"> <option value="monthly">Monthly</option> <option value="weekly">Weekly</option> <option value="daily">Daily</option> </select> </div> <div class="action-panel-control-wrap saved-search-monthly-additional"> <label for="saved-search-monthly-on-day" class="action-panel-label"> Which day? </label> <select id="saved-search-monthly-on-day" class="no-border-panel-selector"> <option value="Sunday">The first Sunday</option> <option value="Monday">The first Monday</option> <option value="Tuesday">The first Tuesday</option> <option value="Wednesday">The first Wednesday</option> <option value="Thursday">The first Thursday</option> <option value="Friday">The first Friday</option> <option value="Saturday">The first Saturday</option> <option value="day">The first day</option> <option value="weekday">The first weekday</option> </select> </div> <div class="action-panel-control-wrap saved-search-weekly-additional"> <label for="saved-search-weekly-on-day" class="action-panel-label"> Which day? </label> <select id="saved-search-weekly-on-day" class="no-border-panel-selector saved-search-weekly-on-day"> <option value="Sunday">Sunday</option> <option value="Monday">Monday</option> <option value="Tuesday">Tuesday</option> <option value="Wednesday">Wednesday</option> <option value="Thursday">Thursday</option> <option value="Friday">Friday</option> <option value="Saturday">Saturday</option> </select> </div> <div class="action-panel-control-wrap"> <label for="saved-search-report" class="action-panel-label"> Report format: </label> <select id="saved-search-report" class="no-border-panel-selector saved-search-report"> <option value="DocSum">Summary</option> <option value="DocSumText">Summary (text)</option> <option value="Abstract">Abstract</option> <option value="AbstractText">Abstract (text)</option> <option value="MEDLINE">PubMed</option> </select> </div> <div class="action-panel-control-wrap"> <label for="saved-search-amount" class="action-panel-label"> Send at most: </label> <select id="saved-search-amount" class="no-border-panel-selector saved-search-amount"> <option value="1">1 item</option> <option value="5" selected>5 items</option> <option value="10">10 items</option> <option value="20">20 items</option> <option value="50">50 items</option> <option value="100">100 items</option> <option value="200">200 items</option> </select> </div> <div> <input type="checkbox" id="saved-search-send-if-no-result" class="saved-search-send-if-no-result" name="saved-search-send-if-no-result"> <label for="saved-search-send-if-no-result" class="action-panel-label smaller-checkbox"> Send even when there aren't any new results </label> </div> <div class="action-panel-control-wrap option-text-in-email-wrap"> <label for="saved-search-email-text" class="action-panel-label"> Optional text in email: </label> <textarea name="saved-search-email-text" id="saved-search-email-text" class="saved-search-email-text"></textarea> </div> </div> <div class="action-panel-actions"> <button class="action-panel-submit" type="submit" data-loading-label="Saving..." data-ga-category="save_share" data-ga-action="alert" data-ga-label="save"> Save </button> <button class="action-panel-cancel" aria-label="Close 'Your saved search' panel" ref="linksrc=close_saved_search_panel" aria-controls="saved-search-action-panel" aria-expanded="false" data-ga-category="save_share" data-ga-action="alert" data-ga-label="cancel"> Cancel </button> </div> </form> </div> </div> <div id="citation-manager-action-panel" class="citation-manager-action-panel action-panel" aria-hidden="true"> <div class="inner-wrap"> <h2 class="action-panel-heading"> Create a file for external citation management software </h2> <form id="citation-manager-action-panel-form" class="action-panel-content action-form" action="/results-export-ids/" data-by-search-action="/results-export-search-data/" data-by-ids-action="/results-export-ids/" method="post" data-by-search-method="post" data-by-ids-method="post"> <input type="hidden" name="csrfmiddlewaretoken" value="P3cOK6vkfrPgo1HD3GGyUV7O0P9JAFhuB8WKTx6fe5V6ngbUs43qBhuwt4zw1bIW"> <input name="results-format" type="hidden" value="pubmed"/> <div class="action-panel-actions"> <button class="action-panel-submit" type="submit" data-loading-label="Sending..." data-ga-category="save_share" data-ga-action="citation_manager" data-ga-label="save"> Create file </button> <button class="action-panel-cancel" aria-label="Close 'Send citations to citation manager' panel" ref="linksrc=close_citation_manager_panel" aria-controls="citation-manager-action-panel" aria-expanded="false" data-ga-category="save_share" data-ga-action="citation_manager" data-ga-label="cancel"> Cancel </button> </div> </form> </div> </div> <div id="rss-action-panel" class="rss-action-panel action-panel " aria-hidden="true"> <div class="inner-wrap"> <h2 class="action-panel-heading"> Your RSS Feed </h2> <form id="rss-action-panel-form" class="rss-action-panel-form action-panel-content action-form" data-create-rss-feed-url="/create-rss-feed-url/" data-search-form-term-value=""> <input type="hidden" name="csrfmiddlewaretoken" value="P3cOK6vkfrPgo1HD3GGyUV7O0P9JAFhuB8WKTx6fe5V6ngbUs43qBhuwt4zw1bIW"> <div class="action-panel-control-wrap"> <label for="rss-name" class="action-panel-label required-field-asterisk"> Name of RSS Feed: </label> <input maxlength="200" placeholder="Name" type="text" name="rss-name" id="rss-name" class="rss-name" value='' required pattern="[^"&=<>\/]*" title="The following characters are not allowed in the Name field: "&=<>/"> </div> <div class="rss-limit-wrap"> <div class="action-panel-control-wrap action-panel-extra-margin-top"> <label for="rss-limit" class="action-panel-label"> Number of items displayed: </label> <select id="rss-limit" class="no-border-panel-selector rss-limit"> <option value="5">5</option> <option value="10">10</option> <option value="15" selected="selected">15</option> <option value="20">20</option> <option value="50">50</option> <option value="100">100</option> </select> </div> </div> <div class="action-panel-actions"> <button class="action-panel-submit" type="submit" data-loading-label="Creating..." data-ga-category="save_share" data-ga-action="alert" data-ga-label="save"> Create RSS </button> <button class="action-panel-cancel" aria-label="Close 'Your RSS' panel" ref="linksrc=close_rss_panel" aria-controls="rss-action-panel" aria-expanded="false" data-ga-category="save_share" data-ga-action="alert" data-ga-label="cancel"> Cancel </button> </div> <div class="action-panel-control-wrap rss-link-copy-wrap"> <label for="rss-link" class="usa-sr-only">RSS Link</label> <input placeholder="Your RSS Feed Link" type="text" name="rss-link" id="rss-link" class="rss-link" title="RSS Link"> <button type="button" disabled class="rss-link-copy-button disabled" data-ga-category="save_share" data-ga-action="rss" data-ga-label="copy"> Copy </button> </div> </form> </div> </div> </div> </div> <div class="article-page" id="article-page" data-article-pmid="19666581"> <aside class="page-sidebar"> <div class="inner-wrap"> <div class="full-text-links"> <div class="full-view"> <h3 class="title"> Full text links </h3> <div class="full-text-links-list"> <a class="link-item dialog-focus" 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required-field-asterisk"> Name your collection: </label><input type="text" name="add-to-new-collection" id="collections-action-dialog-add-to-new" class="collections-action-add-to-new" pattern="[^"&=<>\/]*" title="The following characters are not allowed in the Name field: "&=<>/" maxlength="100" data-ga-category="collections_button" data-ga-action="create_collection" data-ga-label="non_favorties_collection"><div class="collections-new-name-too-long usa-input-error-message selection-validation-message"> Name must be less than 100 characters </div></div><div class="action-panel-control-wrap existing-collections-controls"><label for="collections-action-dialog-add-to-existing" class="action-panel-label"> Choose a collection: </label><select id="collections-action-dialog-add-to-existing" class="action-panel-selector collections-action-add-to-existing" data-ga-category="collections_button" data-ga-action="select_collection" data-ga-label="($('.collections-action-add-to-existing').val() === 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'Favorites' : 'non_favorites_collection'"></select><div class="collections-retry-load-on-error usa-input-error-message selection-validation-message"> Unable to load your collection due to an error<br><a href="#">Please try again</a></div></div></div><div class="action-panel-actions"><button class="action-panel-submit" type="submit" data-loading-label="Adding..." data-pinger-ignore data-ga-category="collections_button" data-ga-action="click" data-ga-label="add"> Add </button><button class="action-panel-cancel" aria-label="Close 'Add to Collections' panel" ref="linksrc=close_collections_panel" aria-controls="collections-action-panel" aria-expanded="false" data-ga-category="collections_button" data-ga-action="click" data-ga-label="cancel"> Cancel </button></div></form></div></div></div></div><button class="more-actions-button more-actions-dialog-trigger" title="Open dialog with more actions to take" ref="linksrc=more_actions_btn"></button><div class="display-options" 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doi: 10.1073/pnas.0906670106. </span> <span class="secondary-date"> Epub 2009 Jul 28. </span> </div> <h1 class="heading-title"> The molecular basis for impaired hypoxia-induced VEGF expression in diabetic tissues </h1> <div class="inline-authors"> <div class="authors"> <div class="authors-list"> <span class="authors-list-item "><a class="full-name" href="/?term=Thangarajah+H&cauthor_id=19666581" ref="linksrc=author_name_link" data-ga-category="search" data-ga-action="author_link" data-ga-label="Hariharan Thangarajah">Hariharan Thangarajah</a><sup class="affiliation-links"><span class="author-sup-separator"> </span><a class="affiliation-link" title="Department of Surgery, Stanford University School of Medicine, 257 Campus Drive, GK-201, Stanford, CA 94305, USA." href="#full-view-affiliation-1" ref="linksrc=author_aff"> 1 </a></sup><span class="comma">, </span></span><span class="authors-list-item "><a class="full-name" href="/?term=Yao+D&cauthor_id=19666581" ref="linksrc=author_name_link" data-ga-category="search" data-ga-action="author_link" data-ga-label="Dachun Yao">Dachun Yao</a><span class="comma">, </span></span><span class="authors-list-item "><a class="full-name" href="/?term=Chang+EI&cauthor_id=19666581" ref="linksrc=author_name_link" data-ga-category="search" data-ga-action="author_link" data-ga-label="Edward I Chang">Edward I Chang</a><span class="comma">, </span></span><span class="authors-list-item "><a class="full-name" href="/?term=Shi+Y&cauthor_id=19666581" ref="linksrc=author_name_link" data-ga-category="search" data-ga-action="author_link" data-ga-label="Yubin Shi">Yubin Shi</a><span class="comma">, </span></span><span class="authors-list-item "><a class="full-name" href="/?term=Jazayeri+L&cauthor_id=19666581" ref="linksrc=author_name_link" data-ga-category="search" data-ga-action="author_link" data-ga-label="Leila Jazayeri">Leila Jazayeri</a><span class="comma">, </span></span><span class="authors-list-item "><a class="full-name" href="/?term=Vial+IN&cauthor_id=19666581" ref="linksrc=author_name_link" data-ga-category="search" data-ga-action="author_link" data-ga-label="Ivan N Vial">Ivan N Vial</a><span class="comma">, </span></span><span class="authors-list-item "><a class="full-name" href="/?term=Galiano+RD&cauthor_id=19666581" ref="linksrc=author_name_link" data-ga-category="search" data-ga-action="author_link" data-ga-label="Robert D Galiano">Robert D Galiano</a><span class="comma">, </span></span><span class="authors-list-item "><a class="full-name" href="/?term=Du+XL&cauthor_id=19666581" ref="linksrc=author_name_link" data-ga-category="search" data-ga-action="author_link" data-ga-label="Xue-Liang Du">Xue-Liang Du</a><span class="comma">, </span></span><span class="authors-list-item "><a class="full-name" href="/?term=Grogan+R&cauthor_id=19666581" ref="linksrc=author_name_link" data-ga-category="search" data-ga-action="author_link" data-ga-label="Raymon Grogan">Raymon Grogan</a><span 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class="identifier pubmed"> <span class="id-label"> PMID: </span> <strong class="current-id" title="PubMed ID">19666581</strong> </span> </li> <li> <span class="identifier pmc"> <span class="id-label"> PMCID: </span> <a class="id-link" target="_blank" rel="noopener" ref="linksrc=article_id_link&article_id=PMC2726398&id_type=PMC" href="https://pmc.ncbi.nlm.nih.gov/articles/PMC2726398/" data-ga-category="full_text" data-ga-action="PMCID" > PMC2726398 </a> </span> </li> <li> <span class="identifier doi"> <span class="id-label"> DOI: </span> <a class="id-link" target="_blank" rel="noopener" ref="linksrc=article_id_link&article_id=10.1073/pnas.0906670106&id_type=DOI" href="https://doi.org/10.1073/pnas.0906670106" data-ga-category="full_text" data-ga-action="DOI" > 10.1073/pnas.0906670106 </a> </span> </li> </ul> <div class="in-clipboard-label " hidden> Item in Clipboard </div> </div> <div class="short-view" id="short-view-heading"> <h1 class="heading-title"> The molecular basis for impaired hypoxia-induced VEGF expression in diabetic tissues </h1> <div class="short-citation"> <span class="authors-list"> <span class="authors-list-item "><span class="full-name">Hariharan Thangarajah</span><span class="citation-separator"> et al.</span></span> </span> <span class="citation-journal"> Proc Natl Acad Sci U S A<span class="citation-separator">.</span> </span> <span class="date"> <time class="citation-year" datetime="2009">2009</time><span class="citation-separator">.</span> </span> </div> <div class="more-article-details-section with-display-settings"> <button class="more-article-details" id="toggle-article-details" data-alt-text="Hide details" ref="linksrc=toggle_article_details" aria-controls="full-article-details" aria-expanded="false" data-fetch-url="/19666581/long-authors/" data-id-prefix=""> <span class="title">Show details</span> </button> <div class="display-options" data-format-key="format" data-default-format-value="abstract" data-current-format-value="abstract" 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S A"> Search in PubMed </a></li><li><a class="search-in-nlm-catalog-link dropdown-block-link" ref ="linksrc=search_in_nlm_catalog_link" href="https://www.ncbi.nlm.nih.gov/nlmcatalog?term=%22Proc+Natl+Acad+Sci+U+S+A%22%5BTitle+Abbreviation%5D" data-ga-category="search_catalog" data-ga-action="journal_link" data-ga-label="Proc Natl Acad Sci U S A"> Search in NLM Catalog </a></li><li><a class="add-to-search-link dropdown-block-link" ref ="linksrc=add_to_search_link" role="button" data-search-term='"Proc Natl Acad Sci U S A"[jour]' data-ga-category="search" data-ga-action="add_to_search" data-ga-label='"Proc Natl Acad Sci U S A"[jour]' href="#"> Add to Search </a></li></ul></div></div></div><span class="period">. </span><span class="cit">2009 Aug 11;106(32):13505-10.</span> </div> <span class="citation-doi"> doi: 10.1073/pnas.0906670106. </span> <span class="secondary-date"> Epub 2009 Jul 28. </span> </div> <div class="expanded-authors" id="short-view-expanded-authors"> <div class="authors"> <h3 class="title"> Authors </h3> <div class="authors-list"> <span class="authors-list-item "><a class="full-name" href="/?term=Thangarajah+H&cauthor_id=19666581" ref="linksrc=author_name_link" data-ga-category="search" data-ga-action="author_link" data-ga-label="Hariharan Thangarajah">Hariharan Thangarajah</a><sup class="affiliation-links"><span class="author-sup-separator"> </span><a class="affiliation-link" title="Department of Surgery, Stanford University School of Medicine, 257 Campus Drive, GK-201, Stanford, CA 94305, USA." href="#short-view-affiliation-1" ref="linksrc=author_aff"> 1 </a></sup><span class="comma">, </span></span><span class="authors-list-item "><a class="full-name" href="/?term=Yao+D&cauthor_id=19666581" ref="linksrc=author_name_link" data-ga-category="search" data-ga-action="author_link" data-ga-label="Dachun Yao">Dachun Yao</a><span class="comma">, </span></span><span class="authors-list-item "><a class="full-name" href="/?term=Chang+EI&cauthor_id=19666581" ref="linksrc=author_name_link" data-ga-category="search" data-ga-action="author_link" data-ga-label="Edward I Chang">Edward I Chang</a><span class="comma">, </span></span><span class="authors-list-item "><a class="full-name" href="/?term=Shi+Y&cauthor_id=19666581" ref="linksrc=author_name_link" data-ga-category="search" data-ga-action="author_link" data-ga-label="Yubin Shi">Yubin Shi</a><span class="comma">, </span></span><span class="authors-list-item "><a class="full-name" href="/?term=Jazayeri+L&cauthor_id=19666581" ref="linksrc=author_name_link" data-ga-category="search" data-ga-action="author_link" data-ga-label="Leila Jazayeri">Leila Jazayeri</a><span class="comma">, </span></span><span class="authors-list-item "><a class="full-name" href="/?term=Vial+IN&cauthor_id=19666581" ref="linksrc=author_name_link" data-ga-category="search" data-ga-action="author_link" data-ga-label="Ivan N Vial">Ivan N Vial</a><span class="comma">, </span></span><span class="authors-list-item "><a class="full-name" href="/?term=Galiano+RD&cauthor_id=19666581" ref="linksrc=author_name_link" data-ga-category="search" data-ga-action="author_link" data-ga-label="Robert D Galiano">Robert D Galiano</a><span class="comma">, </span></span><span class="authors-list-item "><a class="full-name" href="/?term=Du+XL&cauthor_id=19666581" ref="linksrc=author_name_link" data-ga-category="search" data-ga-action="author_link" data-ga-label="Xue-Liang Du">Xue-Liang Du</a><span class="comma">, </span></span><span class="authors-list-item "><a class="full-name" href="/?term=Grogan+R&cauthor_id=19666581" ref="linksrc=author_name_link" data-ga-category="search" data-ga-action="author_link" data-ga-label="Raymon Grogan">Raymon Grogan</a><span class="comma">, </span></span><span class="authors-list-item "><a class="full-name" href="/?term=Galvez+MG&cauthor_id=19666581" ref="linksrc=author_name_link" data-ga-category="search" data-ga-action="author_link" data-ga-label="Michael G Galvez">Michael G Galvez</a><span class="comma">, </span></span><span class="authors-list-item "><a class="full-name" href="/?term=Januszyk+M&cauthor_id=19666581" ref="linksrc=author_name_link" data-ga-category="search" data-ga-action="author_link" data-ga-label="Michael Januszyk">Michael Januszyk</a><span class="comma">, </span></span><span class="authors-list-item "><a class="full-name" href="/?term=Brownlee+M&cauthor_id=19666581" ref="linksrc=author_name_link" data-ga-category="search" data-ga-action="author_link" data-ga-label="Michael Brownlee">Michael Brownlee</a><span class="comma">, </span></span><span class="authors-list-item "><a class="full-name" href="/?term=Gurtner+GC&cauthor_id=19666581" ref="linksrc=author_name_link" data-ga-category="search" data-ga-action="author_link" data-ga-label="Geoffrey C Gurtner">Geoffrey C Gurtner</a></span> </div> </div> <div class="affiliations"> <h3 class="title"> Affiliation </h3> <ul class="item-list"> <li data-affiliation-id="short-view-affiliation-1" id="short-view-affiliation-1" ><sup class="key">1</sup> Department of Surgery, Stanford University School of Medicine, 257 Campus Drive, GK-201, Stanford, CA 94305, USA.</li> </ul> </div> </div> <ul class="identifiers" id="short-view-identifiers"> <li> <span class="identifier pubmed"> <span class="id-label"> PMID: </span> <strong class="current-id" title="PubMed ID">19666581</strong> </span> </li> <li> <span class="identifier pmc"> <span class="id-label"> PMCID: </span> <a class="id-link" target="_blank" rel="noopener" ref="linksrc=article_id_link&article_id=PMC2726398&id_type=PMC" href="https://pmc.ncbi.nlm.nih.gov/articles/PMC2726398/" data-ga-category="full_text" data-ga-action="PMCID" > PMC2726398 </a> </span> </li> <li> <span class="identifier doi"> <span class="id-label"> DOI: </span> <a class="id-link" target="_blank" rel="noopener" ref="linksrc=article_id_link&article_id=10.1073/pnas.0906670106&id_type=DOI" href="https://doi.org/10.1073/pnas.0906670106" data-ga-category="full_text" data-ga-action="DOI" > 10.1073/pnas.0906670106 </a> </span> </li> </ul> <div class="in-clipboard-label " hidden> Item in Clipboard </div> </div> </div> </header> <div class="actions-buttons inline"><div class="inner-wrap"><button class="full-text-links-button full-text-links-dialog-trigger" title="Open dialog with full text links" ref="linksrc=full_text_links"> Full text links </button><button class="citation-button citation-dialog-trigger" aria-label="Open dialog with citation text in different styles" data-ga-category="save_share" data-ga-action="cite" data-ga-label="open" data-all-citations-url="/19666581/citations/" data-citation-style="nlm" data-pubmed-format-link="/19666581/export/"><span class="button-label">Cite</span></button><button class="more-actions-button more-actions-dialog-trigger" title="Open dialog with more actions to take" ref="linksrc=more_actions_btn"></button><div class="display-options" data-format-key="format" data-default-format-value="abstract" data-current-format-value="abstract" role="region"><button class="trigger usa-button" title="Change format" data-ga-category="display_options" data-ga-action="display_options_dialog"><span class="button-label">Display options</span></button><div class="dropdown" hidden><div class="title"> Display options </div><div class="content"><div class="format-container"><span class="option-label"> Format </span><select name="format" data-initial-value="abstract" aria-label="Display format" id="inline-actions-display-format"><option value="abstract">Abstract</option><option value="pubmed">PubMed</option><option value="pmid">PMID</option></select></div></div></div></div></div></div> <div class="abstract" id="abstract"> <h2 class="title"> Abstract </h2> <div class="abstract-content selected" id="eng-abstract"> <p> Diabetes is associated with poor outcomes following acute vascular occlusive events. This results in part from a failure to form adequate compensatory microvasculature in response to ischemia. Since vascular endothelial growth factor (VEGF) is an essential mediator of neovascularization, we examined whether hypoxic up-regulation of VEGF was impaired in diabetes. Both fibroblasts isolated from type 2 diabetic patients, and normal fibroblasts exposed chronically to high glucose, were defective in their capacity to up-regulate VEGF in response to hypoxia. In vivo, diabetic animals demonstrated an impaired ability to increase VEGF production in response to soft tissue ischemia. This resulted from a high glucose-induced decrease in transactivation by the transcription factor hypoxia-inducible factor-1alpha (HIF-1alpha), which mediates hypoxia-stimulated VEGF expression. Decreased HIF-1alpha functional activity was specifically caused by impaired HIF-1alpha binding to the coactivator p300. We identify covalent modification of p300 by the dicarbonyl metabolite methylglyoxal as being responsible for this decreased association. Administration of deferoxamine abrogated methylglyoxal conjugation, normalizing both HIF-1alpha/p300 interaction and transactivation by HIF-1alpha. In diabetic mice, deferoxamine promoted neovascularization and enhanced wound healing. These findings define molecular defects that underlie impaired VEGF production in diabetic tissues and offer a promising direction for therapeutic intervention. </p> </div> </div> <p class="disclaimer" id="disclaimer"> <a href="/disclaimer/" target="_blank" ga_category="literature_resources" ga_action="disclaimer_link" ga_label="under_abstract">PubMed Disclaimer</a> </p> <div class="conflict-of-interest" id="conflict-of-interest"> <h2 class="title"> Conflict of interest statement </h2> <div class="statement"> <p xmlns:xlink="http://www.w3.org/1999/xlink" xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:p1="http://pubmed.gov/pub-one">The authors declare no conflict of interest.</p> </div> </div> <div class="figures" id="figures"> <h2 class="title"> Figures </h2> <div class="figures-list" id="slides-container" itemscope itemtype="http://schema.org/ImageGallery"> <figure class="figure-item " itemscope itemtype="http://schema.org/ImageObject" itemprop="associatedMedia" data-slide-index="0" data-label-slug="fig-1"> <a class="figure-link" href="https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7341/2726398/e239a2b7ee0a/zpq9990989330001.jpg" itemprop="contentUrl" aria-describedby="figure-caption-0" role="button" data-image-width="427" data-image-height="707" data-image-alt="Fig. 1." data-pmc-id="PMC2726398" data-figure-id="F1"> <img class="figure-thumb" itemprop="thumbnail" id="article-image-0" src="https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7341/2726398/e5c48745f54b/zpq9990989330001.gif" alt="Fig. 1." /> </a> <meta itemprop="width" itemtype="http://schema.org/ImageObject" content="427"> <meta itemprop="height" itemtype="http://schema.org/ImageObject" content="707"> <div class="figure-caption figure-caption-text" itemtype="http://schema.org/ImageObject" itemprop="caption" aria-hidden="true"> <div class="caption-wrap"> <strong class="figure-label"> <p> Fig. 1. </p> </strong> <div class="figure-caption-contents"><p> Diabetes and prolonged exposure to… </p></div> </div> </div> <div class="figure-caption-medium figure-caption-text" aria-hidden="true"> <strong class="figure-label"> <p> Fig. 1. </p> </strong> <div class="figure-caption-contents"><p> Diabetes and prolonged exposure to high glucose impair hypoxic induction of VEGF expression.… </p></div> </div> <figcaption id="figure-caption-0" class="figure-caption-full figure-caption-text" itemtype="http://schema.org/ImageObject" itemprop="description"> <strong class="figure-label"> Fig. 1. </strong> <div class="figure-caption-contents">Diabetes and prolonged exposure to high glucose impair hypoxic induction of VEGF expression. Cells were placed in hypoxia (0.5% O<sub>2</sub>) or normoxia (21% O<sub>2</sub>), and levels of VEGF secretion were measured by ELISA. (<i>A</i>) Dermal fibroblasts isolated from diabetic patients produced less VEGF. (<i>B</i>) Fibroblasts from normal human foreskins were cultured chronically (4 weeks) in low glucose (LG) or high glucose (HG). VEGF protein expression was significantly attenuated in cells grown in HG and exposed to hypoxia. (<i>C</i>) Schematic depicting murine ischemic model used. Tissue oxygen tensions are highest in the most proximal (cranial) part of the tissue bed [A] and decrease in a gradient to the most distal (caudal) part [C]. (<i>D</i>) VEGF levels in ischemic skin segments of normal mice measured 24 and 72 h after ischemic induction. (<i>E</i>) VEGF protein levels in ischemic skin tissue from <i>db/db</i> mice. All values represent mean ± SEM. *, <i>P</i> < 0.05 vs. baseline. ‡, <i>P</i> < 0.05 vs. zone A. ¶, <i>P</i> < 0.05 vs. 24 h. <i>n</i> = 6 for all panels. Nl, normal skin.</div> </figcaption> </figure> <figure class="figure-item " itemscope itemtype="http://schema.org/ImageObject" itemprop="associatedMedia" data-slide-index="1" data-label-slug="fig-2"> <a class="figure-link" href="https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7341/2726398/ee9e9c221cfb/zpq9990989330002.jpg" itemprop="contentUrl" aria-describedby="figure-caption-1" role="button" data-image-width="444" data-image-height="494" data-image-alt="Fig. 2." data-pmc-id="PMC2726398" data-figure-id="F2"> <img class="figure-thumb" itemprop="thumbnail" id="article-image-1" src="https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7341/2726398/4e5c4e630a03/zpq9990989330002.gif" alt="Fig. 2." /> </a> <meta itemprop="width" itemtype="http://schema.org/ImageObject" content="444"> <meta itemprop="height" itemtype="http://schema.org/ImageObject" content="494"> <div class="figure-caption figure-caption-text" itemtype="http://schema.org/ImageObject" itemprop="caption" aria-hidden="true"> <div class="caption-wrap"> <strong class="figure-label"> <p> Fig. 2. </p> </strong> <div class="figure-caption-contents"><p> Hyperglycemia-induced impairment in HIF-1 transactivation… </p></div> </div> </div> <div class="figure-caption-medium figure-caption-text" aria-hidden="true"> <strong class="figure-label"> <p> Fig. 2. </p> </strong> <div class="figure-caption-contents"><p> Hyperglycemia-induced impairment in HIF-1 transactivation occurs as a result of decreased HIF-1α binding… </p></div> </div> <figcaption id="figure-caption-1" class="figure-caption-full figure-caption-text" itemtype="http://schema.org/ImageObject" itemprop="description"> <strong class="figure-label"> Fig. 2. </strong> <div class="figure-caption-contents">Hyperglycemia-induced impairment in HIF-1 transactivation occurs as a result of decreased HIF-1α binding to p300. (<i>A</i>) Plasmids containing a full-length VEGF-A promoter (pVEGF-<i>kpnI</i>-luc) or the hypoxia response element for the enolase gene (p2.1), both linked to firefly luciferase, were transfected into cells and subsequently exposed to hypoxia. HG exposure decreased HIF-1 transactivation with use of either plasmid. (<i>B</i>) HAECs were treated for 5 days with LG, HG, or HG after infection of GLO1 adenovirus (HG/GLO1). After exposure to hypoxia for 18 h, cell lysates were collected for immunoprecipitation (IP) of p300 and subsequently immunoblotted (IB) for p300, methylglyoxal (MG), or HIF-1α. β-actin was used as an input control (shown in red typeface). (<i>C</i>) Western blot quantitation of panel <i>B</i>. (<i>D</i>) HAECs were transfected with plasmids containing the HIF-1α-CAD and the p300-CH1 domain together with a reporter plasmid containing a Gal4-binding motif upstream of a firefly luciferase reporter gene. Cells were grown in LG or HG and exposed to normoxia or hypoxia, and the level of luciferase reporter activity subsequently measured. Impaired HIF-1α/p300 binding in HG was completely reversed with GLO1 treatment. *, <i>P</i> < 0.05 vs. LG group. <i>n</i> = 3.</div> </figcaption> </figure> <figure class="figure-item " itemscope itemtype="http://schema.org/ImageObject" itemprop="associatedMedia" data-slide-index="2" data-label-slug="fig-3"> <a class="figure-link" href="https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7341/2726398/5f540c1dc98e/zpq9990989330003.jpg" itemprop="contentUrl" aria-describedby="figure-caption-2" role="button" data-image-width="454" data-image-height="463" data-image-alt="Fig. 3." data-pmc-id="PMC2726398" data-figure-id="F3"> <img class="figure-thumb" itemprop="thumbnail" id="article-image-2" src="https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7341/2726398/8992ca022482/zpq9990989330003.gif" alt="Fig. 3." /> </a> <meta itemprop="width" itemtype="http://schema.org/ImageObject" content="454"> <meta itemprop="height" itemtype="http://schema.org/ImageObject" content="463"> <div class="figure-caption figure-caption-text" itemtype="http://schema.org/ImageObject" itemprop="caption" aria-hidden="true"> <div class="caption-wrap"> <strong class="figure-label"> <p> Fig. 3. </p> </strong> <div class="figure-caption-contents"><p> High glucose-induced methylglyoxal modification of… </p></div> </div> </div> <div class="figure-caption-medium figure-caption-text" aria-hidden="true"> <strong class="figure-label"> <p> Fig. 3. </p> </strong> <div class="figure-caption-contents"><p> High glucose-induced methylglyoxal modification of p300 at R354 decreases association of p300 with… </p></div> </div> <figcaption id="figure-caption-2" class="figure-caption-full figure-caption-text" itemtype="http://schema.org/ImageObject" itemprop="description"> <strong class="figure-label"> Fig. 3. </strong> <div class="figure-caption-contents">High glucose-induced methylglyoxal modification of p300 at R354 decreases association of p300 with HIF-1α. (<i>A</i>) HAECs were transfected with either Gal4(AD) wild-type p300 or p300 single-mutant 354(Q), followed by treatment for 5 days in LG or HG, and subsequent exposure to 18 h of hypoxia. Cell lysates were collected for IP of Gal4(p300) and IB for Gal4(p300) and methylglyoxal (MG). (<i>B</i>) Western blot quantitation of panel <i>A</i>. (<i>C</i>) HAECs were treated as in panel <i>A</i>. Lysates were collected for IP of HIF-1α and IB for Gal4(p300) and HIF-1α. (<i>D</i>) Western blot quantitation of panel <i>C</i>. Immunoprecipitation inputs (shown in red typeface) were used as loading controls. *, <i>P</i> < 0.05 vs. LG group. <i>n</i> = 3. AD, activation domain.</div> </figcaption> </figure> <figure class="figure-item " itemscope itemtype="http://schema.org/ImageObject" itemprop="associatedMedia" data-slide-index="3" data-label-slug="fig-4"> <a class="figure-link" href="https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7341/2726398/9bfd9c732df9/zpq9990989330004.jpg" itemprop="contentUrl" aria-describedby="figure-caption-3" role="button" data-image-width="462" data-image-height="660" data-image-alt="Fig. 4." data-pmc-id="PMC2726398" data-figure-id="F4"> <img class="figure-thumb" itemprop="thumbnail" id="article-image-3" src="https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7341/2726398/bd76b34d043d/zpq9990989330004.gif" alt="Fig. 4." /> </a> <meta itemprop="width" itemtype="http://schema.org/ImageObject" content="462"> <meta itemprop="height" itemtype="http://schema.org/ImageObject" content="660"> <div class="figure-caption figure-caption-text" itemtype="http://schema.org/ImageObject" itemprop="caption" aria-hidden="true"> <div class="caption-wrap"> <strong class="figure-label"> <p> Fig. 4. </p> </strong> <div class="figure-caption-contents"><p> DFO corrects HIF-1α/p300 binding and… </p></div> </div> </div> <div class="figure-caption-medium figure-caption-text" aria-hidden="true"> <strong class="figure-label"> <p> Fig. 4. </p> </strong> <div class="figure-caption-contents"><p> DFO corrects HIF-1α/p300 binding and augments HIF-1 transactivation and VEGF expression in high… </p></div> </div> <figcaption id="figure-caption-3" class="figure-caption-full figure-caption-text" itemtype="http://schema.org/ImageObject" itemprop="description"> <strong class="figure-label"> Fig. 4. </strong> <div class="figure-caption-contents">DFO corrects HIF-1α/p300 binding and augments HIF-1 transactivation and VEGF expression in high glucose culture. (<i>A</i>) HAECs cultured with LG, HG, or HG with DFO (HG/DFO) were exposed to hypoxia and evaluated by mammalian 2-hybrid assay for HIF-1α/p300 binding. DFO treatment augmented HIF-1α/p300 binding in cells exposed to HG. (<i>B</i>) IP/WB of p300 and HIF-1α following treatment described in panel <i>A</i>. β-actin was used as an input control (shown in red typeface). (<i>C</i>) Western blot quantitation of panel <i>B</i>. (<i>D</i>) HIF-1 transactivation analyzed with the 5× hypoxia response element construct described in the Results section. DFO increased HIF-1-mediated luciferase activity in cells exposed to HG in mouse embryonic fibroblasts (MEFs). (<i>E</i>) VEGF ELISA demonstrating DFO's augmentation of VEGF expression by MEFs cultured in HG. *, <i>P</i> < 0.05 vs. HG/DFO group. <i>n</i> = 3.</div> </figcaption> </figure> <figure class="figure-item " itemscope itemtype="http://schema.org/ImageObject" itemprop="associatedMedia" data-slide-index="4" data-label-slug="fig-5"> <a class="figure-link" href="https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7341/2726398/3b959f9effd8/zpq9990989330005.jpg" itemprop="contentUrl" aria-describedby="figure-caption-4" role="button" data-image-width="486" data-image-height="418" data-image-alt="Fig. 5." data-pmc-id="PMC2726398" data-figure-id="F5"> <img class="figure-thumb" itemprop="thumbnail" id="article-image-4" src="https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7341/2726398/c40c057c453b/zpq9990989330005.gif" alt="Fig. 5." /> </a> <meta itemprop="width" itemtype="http://schema.org/ImageObject" content="486"> <meta itemprop="height" itemtype="http://schema.org/ImageObject" content="418"> <div class="figure-caption figure-caption-text" itemtype="http://schema.org/ImageObject" itemprop="caption" aria-hidden="true"> <div class="caption-wrap"> <strong class="figure-label"> <p> Fig. 5. </p> </strong> <div class="figure-caption-contents"><p> DFO decreases ROS generation, prevents… </p></div> </div> </div> <div class="figure-caption-medium figure-caption-text" aria-hidden="true"> <strong class="figure-label"> <p> Fig. 5. </p> </strong> <div class="figure-caption-contents"><p> DFO decreases ROS generation, prevents methylglyoxal modification of p300, and increases VEGF expression… </p></div> </div> <figcaption id="figure-caption-4" class="figure-caption-full figure-caption-text" itemtype="http://schema.org/ImageObject" itemprop="description"> <strong class="figure-label"> Fig. 5. </strong> <div class="figure-caption-contents">DFO decreases ROS generation, prevents methylglyoxal modification of p300, and increases VEGF expression in high glucose culture. HAECs were treated for 5 days in LG, HG, HG with DFO (HG/DFO), HG with DMOG (HG/DMOG), or HG with DFO and DMOG (HG/DFO/DMOG). The following evaluations were then performed: (<i>A</i>) ROS generation, (<i>B</i>) IP/WB of p300 modification by methylglyoxal (MG), and (<i>C</i>) VEGF mRNA expression. *, <i>P</i> < 0.05 vs. LG group. <i>n</i> = 3.</div> </figcaption> </figure> <figure class="figure-item " itemscope itemtype="http://schema.org/ImageObject" itemprop="associatedMedia" data-slide-index="5" data-label-slug="fig-6"> <a class="figure-link" href="https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7341/2726398/0a2cbeae5eee/zpq9990989330006.jpg" itemprop="contentUrl" aria-describedby="figure-caption-5" role="button" data-image-width="500" data-image-height="1222" data-image-alt="Fig. 6." data-pmc-id="PMC2726398" data-figure-id="F6"> <img class="figure-thumb" itemprop="thumbnail" id="article-image-5" src="https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7341/2726398/6f9131158b86/zpq9990989330006.gif" alt="Fig. 6." /> </a> <meta itemprop="width" itemtype="http://schema.org/ImageObject" content="500"> <meta itemprop="height" itemtype="http://schema.org/ImageObject" content="1222"> <div class="figure-caption figure-caption-text" itemtype="http://schema.org/ImageObject" itemprop="caption" aria-hidden="true"> <div class="caption-wrap"> <strong class="figure-label"> <p> Fig. 6. </p> </strong> <div class="figure-caption-contents"><p> DFO enhances wound healing and… </p></div> </div> </div> <div class="figure-caption-medium figure-caption-text" aria-hidden="true"> <strong class="figure-label"> <p> Fig. 6. </p> </strong> <div class="figure-caption-contents"><p> DFO enhances wound healing and neovascularization in diabetic mice. Full-thickness skin wounds on… </p></div> </div> <figcaption id="figure-caption-5" class="figure-caption-full figure-caption-text" itemtype="http://schema.org/ImageObject" itemprop="description"> <strong class="figure-label"> Fig. 6. </strong> <div class="figure-caption-contents">DFO enhances wound healing and neovascularization in diabetic mice. Full-thickness skin wounds on diabetic mice were treated with every other day topical applications of 500 μM DFO, 1,000 μM DFO, or PBS. (<i>A</i>) Photographs of representative wounds for mice treated with PBS or 1,000 μM DFO. Wound resurfacing occurred at day 13 in the DFO-treated group versus day 23 in PBS-treated controls. (<i>B</i>) Graphical depiction of wound area as a function of time. DFO accelerated wound healing in a dose-dependent manner. (<i>C</i>) H&E stains of wound tissue at 7 days post-wounding showing increased granulation tissue in the wounds of DFO-treated animals. White borders delineate initial wound edges, and yellow borders indicate wound edges at day 7. (<i>D</i>) DFO- and PBS-treated mice were analyzed at 7 days post-wounding for vascularity (as assessed by CD31 immunohistochemistry). (<i>E</i>) Numbers of CD31-positive vessels per HPF in DFO-treated (1,000 μM) and PBS-treated mice at days 7, 13, and 21 post-wounding. (<i>F</i>) Wound tissue VEGF concentration at 7 days post-wounding for DFO-treated (1,000 μM) and PBS-treated mice. *, <i>P</i> < 0.05 vs. PBS group. <i>n</i> = 8.</div> </figcaption> </figure> </div>  <div class="pswp figures-dialog" id="figures-dialog" tabindex="-1" role="dialog" aria-hidden="true" data-image-gallery-uid="article-figures" aria-label="Figures Dialog">  <div class="pswp__bg"></div>  <div class="pswp__scroll-wrap">  <div class="pswp__container"> <div class="pswp__item"></div> <div class="pswp__item"></div> <div class="pswp__item"></div> </div>  <div class="pswp__ui pswp__ui--hidden"> <div class="pswp__top-bar">  <div class="pswp__counter"></div> <button class="pswp__button pswp__button--close" title="Close (Esc)"></button> <button class="pswp__button pswp__button--share" title="Share"></button> <button class="pswp__button pswp__button--fs" title="Toggle fullscreen"></button> <button class="pswp__button pswp__button--zoom" title="Zoom in/out"></button>   <div class="pswp__preloader"> <div class="pswp__preloader__icn"> <div class="pswp__preloader__cut"> <div class="pswp__preloader__donut"></div> </div> </div> </div> </div> <div class="pswp__share-modal pswp__share-modal--hidden pswp__single-tap"> <div class="pswp__share-tooltip"></div> </div> <button class="pswp__button pswp__button--arrow--left" title="Previous (arrow left)"> </button> <button class="pswp__button pswp__button--arrow--right" title="Next (arrow right)"> </button> <div class="pswp__caption"> <div class="pswp__caption__center"></div> </div> </div> </div> </div> <div class="figure-dialog-caption"> <div class="figure-caption-link-container"> <a class="figure-caption-link" href="#">See this image and copyright information in PMC</a> </div> <div class="figure-caption-center" data-expand-title="click to show full caption" data-collapse-title="click to hide full caption"> </div> <button class="figure-caption-toggle-btn" aria-label="show full caption" data-expand-text="show full caption" data-collapse-text="hide full caption">  </button> </div> </div> <div class="similar-articles" id="similar"> <h2 class="title"> Similar articles </h2> <ul class="articles-list" id="similar-articles-list"> <li class="full-docsum"> <div class="docsum-content" style="display:inline;"> <a class="docsum-title" href="/23726275/" ref="article_id=23726275&linksrc=similar_articles_link&ordinalpos=1" data-ga-category="similar_article" data-ga-action="23726275" data-ga-label=""> Deferoxamine enhances neovascularization and accelerates wound healing in diabetic rats via the accumulation of hypoxia-inducible factor-1α. </a> <div class="docsum-citation full-citation"> <span class="docsum-authors full-authors">Hou Z, Nie C, Si Z, Ma Y.</span> <span class="docsum-authors short-authors">Hou Z, et al.</span> <span class="docsum-journal-citation full-journal-citation">Diabetes Res Clin Pract. 2013 Jul;101(1):62-71. doi: 10.1016/j.diabres.2013.04.012. 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Lifetime costs of complications resulting from type 2 diabetes in the U.S. Diabetes Care. 2002;25:476–481. - <a class="reference-link" href="/11874933/" ref="linksrc=references_link&ordinalpos=1" data-ga-category="reference" data-ga-action="11874933" > PubMed </a> </li> </ol> </li> <li> <ol class="references-and-notes-list"> <li class="skip-numbering" value="1"> Norhammar A, et al. Glucose metabolism in patients with acute myocardial infarction and no previous diagnosis of diabetes mellitus: A prospective study. Lancet. 2002;359:2140–2144. - <a class="reference-link" href="/12090978/" ref="linksrc=references_link&ordinalpos=1" data-ga-category="reference" data-ga-action="12090978" > PubMed </a> </li> </ol> </li> <li> <ol class="references-and-notes-list"> <li class="skip-numbering" value="1"> Abaci A, et al. Effect of diabetes mellitus on formation of coronary collateral vessels. 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ref="linksrc=search_in_pubmed_keyword_link&mesh="Diabetes Mellitus, Experimental/metabolism"[MeSH]" data-ga-category="search" data-ga-action="mesh_term" data-ga-label="Diabetes Mellitus, Experimental / metabolism"> Search in PubMed </a></li><li><a class="search-in-mesh-link dropdown-block-link" ref="linksrc=search_in_mesh_link" href="https://www.ncbi.nlm.nih.gov/mesh?term=Diabetes+Mellitus%2C+Experimental" data-ga-category="search_mesh" data-ga-action="mesh_term_link" data-ga-label="Diabetes Mellitus, Experimental / metabolism"> Search in MeSH </a></li><li><a class="add-to-search-link dropdown-block-link" ref="linksrc=add_to_search_link" role="button" data-search-term=""Diabetes Mellitus, Experimental/metabolism"[MeSH]" data-ga-category="search" data-ga-action="add_to_search" data-ga-label=""Diabetes Mellitus, Experimental/metabolism"[MeSH]" href="#"> Add to Search </a></li></ul></div></div></div></li><li><div class="keyword-actions dropdown-block"><button class="keyword-actions-trigger trigger keyword-link" aria-label="Toggle dropdown menu for keyword Diabetes Mellitus, Experimental / pathology" tabindex="0" aria-controls="keyword-actions-mesh-terms-9" aria-expanded="false" data-pinger-ignore> Diabetes Mellitus, Experimental / pathology </button><div id="keyword-actions-mesh-terms-9" class="keyword-actions-dropdown dropdown dropdown-container" hidden aria-label="Dropdown menu for keyword Diabetes Mellitus, Experimental / pathology"><div class="title">Actions</div><div class="content"><ul class="keyword-actions-links"><li><a class="search-in-pubmed-link dropdown-block-link" href="/?term=%22Diabetes+Mellitus%2C+Experimental%2Fpathology%22%5BMeSH%5D&sort=date&sort_order=desc" data-href="/?term=%22Diabetes+Mellitus%2C+Experimental%2Fpathology%22%5BMeSH%5D&sort=date&sort_order=desc" ref="linksrc=search_in_pubmed_keyword_link&mesh="Diabetes Mellitus, Experimental/pathology"[MeSH]" data-ga-category="search" data-ga-action="mesh_term" 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href="/?term=%22Hypoxia-Inducible+Factor+1%2C+alpha+Subunit%2Fmetabolism%22%5BMeSH%5D&sort=date&sort_order=desc" data-href="/?term=%22Hypoxia-Inducible+Factor+1%2C+alpha+Subunit%2Fmetabolism%22%5BMeSH%5D&sort=date&sort_order=desc" ref="linksrc=search_in_pubmed_keyword_link&mesh="Hypoxia-Inducible Factor 1, alpha Subunit/metabolism"[MeSH]" data-ga-category="search" data-ga-action="mesh_term" data-ga-label="Hypoxia-Inducible Factor 1, alpha Subunit / metabolism"> Search in PubMed </a></li><li><a class="search-in-mesh-link dropdown-block-link" ref="linksrc=search_in_mesh_link" href="https://www.ncbi.nlm.nih.gov/mesh?term=Hypoxia-Inducible+Factor+1%2C+alpha+Subunit" data-ga-category="search_mesh" data-ga-action="mesh_term_link" data-ga-label="Hypoxia-Inducible Factor 1, alpha Subunit / metabolism"> Search in MeSH </a></li><li><a class="add-to-search-link dropdown-block-link" ref="linksrc=add_to_search_link" role="button" data-search-term=""Hypoxia-Inducible Factor 1, alpha 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id="keyword-actions-mesh-terms-19" class="keyword-actions-dropdown dropdown dropdown-container" hidden aria-label="Dropdown menu for keyword Neovascularization, Pathologic / complications"><div class="title">Actions</div><div class="content"><ul class="keyword-actions-links"><li><a class="search-in-pubmed-link dropdown-block-link" href="/?term=%22Neovascularization%2C+Pathologic%2Fcomplications%22%5BMeSH%5D&sort=date&sort_order=desc" data-href="/?term=%22Neovascularization%2C+Pathologic%2Fcomplications%22%5BMeSH%5D&sort=date&sort_order=desc" ref="linksrc=search_in_pubmed_keyword_link&mesh="Neovascularization, Pathologic/complications"[MeSH]" data-ga-category="search" data-ga-action="mesh_term" data-ga-label="Neovascularization, Pathologic / complications"> Search in PubMed </a></li><li><a class="search-in-mesh-link dropdown-block-link" ref="linksrc=search_in_mesh_link" href="https://www.ncbi.nlm.nih.gov/mesh?term=Neovascularization%2C+Pathologic" data-ga-category="search_mesh" 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Pathologic / pathology"><div class="title">Actions</div><div class="content"><ul class="keyword-actions-links"><li><a class="search-in-pubmed-link dropdown-block-link" href="/?term=%22Neovascularization%2C+Pathologic%2Fpathology%22%5BMeSH%5D&sort=date&sort_order=desc" data-href="/?term=%22Neovascularization%2C+Pathologic%2Fpathology%22%5BMeSH%5D&sort=date&sort_order=desc" ref="linksrc=search_in_pubmed_keyword_link&mesh="Neovascularization, Pathologic/pathology"[MeSH]" data-ga-category="search" data-ga-action="mesh_term" data-ga-label="Neovascularization, Pathologic / pathology"> Search in PubMed </a></li><li><a class="search-in-mesh-link dropdown-block-link" ref="linksrc=search_in_mesh_link" href="https://www.ncbi.nlm.nih.gov/mesh?term=Neovascularization%2C+Pathologic" data-ga-category="search_mesh" data-ga-action="mesh_term_link" data-ga-label="Neovascularization, Pathologic / pathology"> Search in MeSH </a></li><li><a class="add-to-search-link dropdown-block-link" ref="linksrc=add_to_search_link" role="button" data-search-term=""Neovascularization, Pathologic/pathology"[MeSH]" data-ga-category="search" data-ga-action="add_to_search" data-ga-label=""Neovascularization, Pathologic/pathology"[MeSH]" href="#"> Add to Search </a></li></ul></div></div></div></li><li><div class="keyword-actions dropdown-block"><button class="keyword-actions-trigger trigger keyword-link" aria-label="Toggle dropdown menu for keyword Protein Binding / drug effects" tabindex="0" aria-controls="keyword-actions-mesh-terms-21" aria-expanded="false" data-pinger-ignore> Protein Binding / drug effects </button><div id="keyword-actions-mesh-terms-21" class="keyword-actions-dropdown dropdown dropdown-container" hidden aria-label="Dropdown menu for keyword Protein Binding / drug effects"><div class="title">Actions</div><div class="content"><ul class="keyword-actions-links"><li><a class="search-in-pubmed-link dropdown-block-link" href="/?term=%22Protein+Binding%2Fdrug+effects%22%5BMeSH%5D&sort=date&sort_order=desc" data-href="/?term=%22Protein+Binding%2Fdrug+effects%22%5BMeSH%5D&sort=date&sort_order=desc" ref="linksrc=search_in_pubmed_keyword_link&mesh="Protein Binding/drug effects"[MeSH]" data-ga-category="search" data-ga-action="mesh_term" data-ga-label="Protein Binding / drug effects"> Search in PubMed </a></li><li><a class="search-in-mesh-link dropdown-block-link" ref="linksrc=search_in_mesh_link" href="https://www.ncbi.nlm.nih.gov/mesh?term=Protein+Binding" data-ga-category="search_mesh" data-ga-action="mesh_term_link" data-ga-label="Protein Binding / drug effects"> Search in MeSH </a></li><li><a class="add-to-search-link dropdown-block-link" ref="linksrc=add_to_search_link" role="button" data-search-term=""Protein Binding/drug effects"[MeSH]" data-ga-category="search" data-ga-action="add_to_search" data-ga-label=""Protein Binding/drug effects"[MeSH]" href="#"> Add to Search </a></li></ul></div></div></div></li><li><div class="keyword-actions dropdown-block"><button class="keyword-actions-trigger trigger keyword-link" aria-label="Toggle dropdown menu for keyword Pyruvaldehyde / pharmacology" tabindex="0" aria-controls="keyword-actions-mesh-terms-22" aria-expanded="false" data-pinger-ignore> Pyruvaldehyde / pharmacology </button><div id="keyword-actions-mesh-terms-22" class="keyword-actions-dropdown dropdown dropdown-container" hidden aria-label="Dropdown menu for keyword Pyruvaldehyde / pharmacology"><div class="title">Actions</div><div class="content"><ul class="keyword-actions-links"><li><a class="search-in-pubmed-link dropdown-block-link" href="/?term=%22Pyruvaldehyde%2Fpharmacology%22%5BMeSH%5D&sort=date&sort_order=desc" data-href="/?term=%22Pyruvaldehyde%2Fpharmacology%22%5BMeSH%5D&sort=date&sort_order=desc" ref="linksrc=search_in_pubmed_keyword_link&mesh="Pyruvaldehyde/pharmacology"[MeSH]" data-ga-category="search" data-ga-action="mesh_term" 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class="content"><ul class="keyword-actions-links"><li><a class="search-in-pubmed-link dropdown-block-link" href="/?term=%22Transcriptional+Activation%2Fdrug+effects%22%5BMeSH%5D&sort=date&sort_order=desc" data-href="/?term=%22Transcriptional+Activation%2Fdrug+effects%22%5BMeSH%5D&sort=date&sort_order=desc" ref="linksrc=search_in_pubmed_keyword_link&mesh="Transcriptional Activation/drug effects"[MeSH]" data-ga-category="search" data-ga-action="mesh_term" data-ga-label="Transcriptional Activation / drug effects"> Search in PubMed </a></li><li><a class="search-in-mesh-link dropdown-block-link" ref="linksrc=search_in_mesh_link" href="https://www.ncbi.nlm.nih.gov/mesh?term=Transcriptional+Activation" data-ga-category="search_mesh" data-ga-action="mesh_term_link" data-ga-label="Transcriptional Activation / drug effects"> Search in MeSH </a></li><li><a class="add-to-search-link dropdown-block-link" ref="linksrc=add_to_search_link" role="button" data-search-term=""Transcriptional 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keyword-link major" aria-label="Toggle dropdown menu for keyword Vascular Endothelial Growth Factor A / metabolism*" tabindex="0" aria-controls="keyword-actions-mesh-terms-major-26" aria-expanded="false" data-pinger-ignore> Vascular Endothelial Growth Factor A / metabolism* </button><div id="keyword-actions-mesh-terms-major-26" class="keyword-actions-dropdown dropdown dropdown-container" hidden aria-label="Dropdown menu for keyword Vascular Endothelial Growth Factor A / metabolism*"><div class="title">Actions</div><div class="content"><ul class="keyword-actions-links"><li><a class="search-in-pubmed-link dropdown-block-link" href="/?term=%22Vascular+Endothelial+Growth+Factor+A%2Fmetabolism%22%5BMAJR%5D&sort=date&sort_order=desc" data-href="/?term=%22Vascular+Endothelial+Growth+Factor+A%2Fmetabolism%22%5BMAJR%5D&sort=date&sort_order=desc" ref="linksrc=search_in_pubmed_keyword_link&mesh="Vascular Endothelial Growth Factor A/metabolism"[MAJR]" data-ga-category="search" 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metabolism"><div class="title">Actions</div><div class="content"><ul class="keyword-actions-links"><li><a class="search-in-pubmed-link dropdown-block-link" href="/?term=%22p300-CBP+Transcription+Factors%2Fmetabolism%22%5BMeSH%5D&sort=date&sort_order=desc" data-href="/?term=%22p300-CBP+Transcription+Factors%2Fmetabolism%22%5BMeSH%5D&sort=date&sort_order=desc" ref="linksrc=search_in_pubmed_keyword_link&mesh="p300-CBP Transcription Factors/metabolism"[MeSH]" data-ga-category="search" data-ga-action="mesh_term" data-ga-label="p300-CBP Transcription Factors / metabolism"> Search in PubMed </a></li><li><a class="search-in-mesh-link dropdown-block-link" ref="linksrc=search_in_mesh_link" href="https://www.ncbi.nlm.nih.gov/mesh?term=p300-CBP+Transcription+Factors" data-ga-category="search_mesh" data-ga-action="mesh_term_link" data-ga-label="p300-CBP Transcription Factors / metabolism"> Search in MeSH </a></li><li><a class="add-to-search-link dropdown-block-link" ref="linksrc=add_to_search_link" 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Factor 1, alpha Subunit"[nm]" data-ga-category="search" data-ga-action="add_to_search" data-ga-label=""Hypoxia-Inducible Factor 1, alpha Subunit"[nm]" href="#"> Add to Search </a></li></ul></div></div></div></li><li><div class="keyword-actions dropdown-block"><button class="keyword-actions-trigger trigger keyword-link" aria-label="Toggle dropdown menu for keyword Reactive Oxygen Species" tabindex="0" aria-controls="keyword-actions-substances-1" aria-expanded="false" data-pinger-ignore> Reactive Oxygen Species </button><div id="keyword-actions-substances-1" class="keyword-actions-dropdown dropdown dropdown-container" hidden aria-label="Dropdown menu for keyword Reactive Oxygen Species"><div class="title">Actions</div><div class="content"><ul class="keyword-actions-links"><li><a class="search-in-pubmed-link dropdown-block-link" href="/?term=%22Reactive+Oxygen+Species%22%5Bnm%5D&sort=date&sort_order=desc" data-href="/?term=%22Reactive+Oxygen+Species%22%5Bnm%5D&sort=date&sort_order=desc" 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tabindex="0" aria-controls="keyword-actions-substances-2" aria-expanded="false" data-pinger-ignore> Vascular Endothelial Growth Factor A </button><div id="keyword-actions-substances-2" class="keyword-actions-dropdown dropdown dropdown-container" hidden aria-label="Dropdown menu for keyword Vascular Endothelial Growth Factor A"><div class="title">Actions</div><div class="content"><ul class="keyword-actions-links"><li><a class="search-in-pubmed-link dropdown-block-link" href="/?term=%22Vascular+Endothelial+Growth+Factor+A%22%5Bnm%5D&sort=date&sort_order=desc" data-href="/?term=%22Vascular+Endothelial+Growth+Factor+A%22%5Bnm%5D&sort=date&sort_order=desc" ref="linksrc=search_in_pubmed_keyword_link&keyword="Vascular Endothelial Growth Factor A"[nm]" data-ga-category="search" data-ga-action="substance" data-ga-label="Vascular Endothelial Growth Factor A"> Search in PubMed </a></li><li><a class="search-in-mesh-link dropdown-block-link" ref="linksrc=search_in_mesh_link" href="https://www.ncbi.nlm.nih.gov/mesh?term=%22Vascular+Endothelial+Growth+Factor+A%22" data-ga-category="search_mesh" data-ga-action="substance_link" data-ga-label="Vascular Endothelial Growth Factor A"> Search in MeSH </a></li><li><a class="add-to-search-link dropdown-block-link" ref="linksrc=add_to_search_link" role="button" data-search-term=""Vascular Endothelial Growth Factor A"[nm]" data-ga-category="search" data-ga-action="add_to_search" data-ga-label=""Vascular Endothelial Growth Factor A"[nm]" href="#"> Add to Search </a></li></ul></div></div></div></li><li><div class="keyword-actions dropdown-block"><button class="keyword-actions-trigger trigger keyword-link" aria-label="Toggle dropdown menu for keyword Pyruvaldehyde" tabindex="0" aria-controls="keyword-actions-substances-3" aria-expanded="false" data-pinger-ignore> Pyruvaldehyde </button><div id="keyword-actions-substances-3" class="keyword-actions-dropdown dropdown dropdown-container" hidden aria-label="Dropdown menu for 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Glucose </button><div id="keyword-actions-substances-5" class="keyword-actions-dropdown dropdown dropdown-container" hidden aria-label="Dropdown menu for keyword Glucose"><div class="title">Actions</div><div class="content"><ul class="keyword-actions-links"><li><a class="search-in-pubmed-link dropdown-block-link" href="/?term=%22Glucose%22%5Bnm%5D&sort=date&sort_order=desc" data-href="/?term=%22Glucose%22%5Bnm%5D&sort=date&sort_order=desc" ref="linksrc=search_in_pubmed_keyword_link&keyword="Glucose"[nm]" data-ga-category="search" data-ga-action="substance" data-ga-label="Glucose"> Search in PubMed </a></li><li><a class="search-in-mesh-link dropdown-block-link" ref="linksrc=search_in_mesh_link" href="https://www.ncbi.nlm.nih.gov/mesh?term=%22Glucose%22" data-ga-category="search_mesh" data-ga-action="substance_link" data-ga-label="Glucose"> Search in MeSH </a></li><li><a class="add-to-search-link dropdown-block-link" ref="linksrc=add_to_search_link" role="button" 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The molecular basis for impaired hypoxia-induced VEGF expression in diabetic tissues - PubMed