Enhanced Lymph Vessel Density, Remodeling, and Inflammation Are Reflected by Gene Expression Signatures in Dermal Lymphatic Endothelial Cells in Type 2 Diabetes
Identifieur interne : 003D81 ( Pmc/Curation ); précédent : 003D80; suivant : 003D82Enhanced Lymph Vessel Density, Remodeling, and Inflammation Are Reflected by Gene Expression Signatures in Dermal Lymphatic Endothelial Cells in Type 2 Diabetes
Auteurs : Monika Haemmerle [Autriche] ; Thomas Keller [Autriche] ; Gerda Egger [Autriche] ; Helga Schachner [Autriche] ; Carl Walter Steiner [Autriche] ; Dejan Stokic [Autriche] ; Christoph Neumayer [Autriche] ; Markus K. Brown [Autriche] ; Dontscho Kerjaschki [Autriche] ; Brigitte Hantusch [Autriche]Source :
- Diabetes [ 0012-1797 ] ; 2013.
Abstract
Type 2 diabetes is associated with microvascular damage that causes frequent infections in the skin and chronic ulcers as a result of impaired wound healing. To trace the pathological changes, we performed a comprehensive analysis of lymphatic vessels in the skin of type 2 diabetic versus nondiabetic patients. The dermis revealed enhanced lymphatic vessel density, and transcriptional profiling of ex vivo isolated lymphatic endothelial cells (LECs) identified 160 genes differentially expressed between type 2 diabetic and nondiabetic LECs. Bioinformatic analysis of deregulated genes uncovered sets functionally related to inflammation, lymphatic vessel remodeling, lymphangiogenesis, and lipid and small molecule transport. Furthermore, we traced CD68+ macrophage accumulation and concomitant upregulation of tumor necrosis factor-α (TNF-α) levels in type 2 diabetic skin. TNF-α treatment of LECs and its specific blockade in vitro reproduced differential regulation of a gene set that led to enhanced LEC mobility and macrophage attachment, which was mediated by the LEC-derived chemokine CXCL10. This study identifies lymph vessel gene signatures directly correlated with type 2 diabetes skin manifestations. In addition, we provide evidence for paracrine cross-talk fostering macrophage recruitment to LECs as one pathophysiological process that might contribute to aberrant lymphangiogenesis and persistent inflammation in the skin.
Url:
DOI: 10.2337/db12-0844
PubMed: 23423575
PubMed Central: 3712036
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<series><title level="j">Diabetes</title>
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<front><div type="abstract" xml:lang="en"><p>Type 2 diabetes is associated with microvascular damage that causes frequent infections in the skin and chronic ulcers as a result of impaired wound healing. To trace the pathological changes, we performed a comprehensive analysis of lymphatic vessels in the skin of type 2 diabetic versus nondiabetic patients. The dermis revealed enhanced lymphatic vessel density, and transcriptional profiling of ex vivo isolated lymphatic endothelial cells (LECs) identified 160 genes differentially expressed between type 2 diabetic and nondiabetic LECs. Bioinformatic analysis of deregulated genes uncovered sets functionally related to inflammation, lymphatic vessel remodeling, lymphangiogenesis, and lipid and small molecule transport. Furthermore, we traced CD68<sup>+</sup>
macrophage accumulation and concomitant upregulation of tumor necrosis factor-α (TNF-α) levels in type 2 diabetic skin. TNF-α treatment of LECs and its specific blockade in vitro reproduced differential regulation of a gene set that led to enhanced LEC mobility and macrophage attachment, which was mediated by the LEC-derived chemokine CXCL10. This study identifies lymph vessel gene signatures directly correlated with type 2 diabetes skin manifestations. In addition, we provide evidence for paracrine cross-talk fostering macrophage recruitment to LECs as one pathophysiological process that might contribute to aberrant lymphangiogenesis and persistent inflammation in the skin.</p>
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<pmc article-type="research-article"><pmc-dir>properties open_access</pmc-dir>
<front><journal-meta><journal-id journal-id-type="nlm-ta">Diabetes</journal-id>
<journal-id journal-id-type="iso-abbrev">Diabetes</journal-id>
<journal-id journal-id-type="hwp">diabetes</journal-id>
<journal-id journal-id-type="pmc">diabetes</journal-id>
<journal-id journal-id-type="publisher-id">Diabetes</journal-id>
<journal-title-group><journal-title>Diabetes</journal-title>
</journal-title-group>
<issn pub-type="ppub">0012-1797</issn>
<issn pub-type="epub">1939-327X</issn>
<publisher><publisher-name>American Diabetes Association</publisher-name>
</publisher>
</journal-meta>
<article-meta><article-id pub-id-type="pmid">23423575</article-id>
<article-id pub-id-type="pmc">3712036</article-id>
<article-id pub-id-type="publisher-id">0844</article-id>
<article-id pub-id-type="doi">10.2337/db12-0844</article-id>
<article-categories><subj-group subj-group-type="heading"><subject>Original Research</subject>
<subj-group><subject>Pathophysiology</subject>
</subj-group>
</subj-group>
</article-categories>
<title-group><article-title>Enhanced Lymph Vessel Density, Remodeling, and Inflammation Are Reflected by Gene Expression Signatures in Dermal Lymphatic Endothelial Cells in Type 2 Diabetes</article-title>
</title-group>
<contrib-group><contrib contrib-type="author"><name><surname>Haemmerle</surname>
<given-names>Monika</given-names>
</name>
<xref ref-type="aff" rid="aff1"><sup>1</sup>
</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Keller</surname>
<given-names>Thomas</given-names>
</name>
<xref ref-type="aff" rid="aff1"><sup>1</sup>
</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Egger</surname>
<given-names>Gerda</given-names>
</name>
<xref ref-type="aff" rid="aff1"><sup>1</sup>
</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Schachner</surname>
<given-names>Helga</given-names>
</name>
<xref ref-type="aff" rid="aff1"><sup>1</sup>
</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Steiner</surname>
<given-names>Carl Walter</given-names>
</name>
<xref ref-type="aff" rid="aff2"><sup>2</sup>
</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Stokic</surname>
<given-names>Dejan</given-names>
</name>
<xref ref-type="aff" rid="aff3"><sup>3</sup>
</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Neumayer</surname>
<given-names>Christoph</given-names>
</name>
<xref ref-type="aff" rid="aff4"><sup>4</sup>
</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Brown</surname>
<given-names>Markus K.</given-names>
</name>
<xref ref-type="aff" rid="aff1"><sup>1</sup>
</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Kerjaschki</surname>
<given-names>Dontscho</given-names>
</name>
<xref ref-type="aff" rid="aff1"><sup>1</sup>
</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Hantusch</surname>
<given-names>Brigitte</given-names>
</name>
<xref ref-type="aff" rid="aff1"><sup>1</sup>
</xref>
<xref ref-type="corresp" rid="cor1"></xref>
</contrib>
<aff id="aff1"><sup>1</sup>
Clinical Institute of Pathology, Medical University of Vienna, Vienna, Austria</aff>
<aff id="aff2"><sup>2</sup>
Department of Internal Medicine, Division of Rheumatology, Medical University of Vienna, Vienna, Austria</aff>
<aff id="aff3"><sup>3</sup>
Section for Science of Complex Systems, Medical University of Vienna, Vienna, Austria</aff>
<aff id="aff4"><sup>4</sup>
Division of Vascular Surgery, Department of Surgery, Medical University of Vienna, Vienna, Austria</aff>
</contrib-group>
<author-notes><corresp id="cor1">Corresponding author: Brigitte Hantusch, <email>brigitte.hantusch@meduniwien.ac.at</email>
.</corresp>
</author-notes>
<pub-date pub-type="ppub"><month>7</month>
<year>2013</year>
</pub-date>
<pub-date pub-type="epub"><day>14</day>
<month>6</month>
<year>2013</year>
</pub-date>
<volume>62</volume>
<issue>7</issue>
<fpage>2509</fpage>
<lpage>2529</lpage>
<history><date date-type="received"><day>22</day>
<month>6</month>
<year>2012</year>
</date>
<date date-type="accepted"><day>09</day>
<month>2</month>
<year>2013</year>
</date>
</history>
<permissions><copyright-statement>© 2013 by the American Diabetes Association.</copyright-statement>
<copyright-year>2013</copyright-year>
<license license-type="creative-commons"><license-p>Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered. See <ext-link ext-link-type="uri" xlink:href="http://creativecommons.org/licenses/by-nc-nd/3.0/">http://creativecommons.org/licenses/by-nc-nd/3.0/</ext-link>
for details.</license-p>
</license>
</permissions>
<self-uri xlink:title="pdf" xlink:type="simple" xlink:href="2509.pdf"></self-uri>
<abstract><p>Type 2 diabetes is associated with microvascular damage that causes frequent infections in the skin and chronic ulcers as a result of impaired wound healing. To trace the pathological changes, we performed a comprehensive analysis of lymphatic vessels in the skin of type 2 diabetic versus nondiabetic patients. The dermis revealed enhanced lymphatic vessel density, and transcriptional profiling of ex vivo isolated lymphatic endothelial cells (LECs) identified 160 genes differentially expressed between type 2 diabetic and nondiabetic LECs. Bioinformatic analysis of deregulated genes uncovered sets functionally related to inflammation, lymphatic vessel remodeling, lymphangiogenesis, and lipid and small molecule transport. Furthermore, we traced CD68<sup>+</sup>
macrophage accumulation and concomitant upregulation of tumor necrosis factor-α (TNF-α) levels in type 2 diabetic skin. TNF-α treatment of LECs and its specific blockade in vitro reproduced differential regulation of a gene set that led to enhanced LEC mobility and macrophage attachment, which was mediated by the LEC-derived chemokine CXCL10. This study identifies lymph vessel gene signatures directly correlated with type 2 diabetes skin manifestations. In addition, we provide evidence for paracrine cross-talk fostering macrophage recruitment to LECs as one pathophysiological process that might contribute to aberrant lymphangiogenesis and persistent inflammation in the skin.</p>
</abstract>
<counts><page-count count="21"></page-count>
</counts>
</article-meta>
</front>
</pmc>
</record>
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