Transcriptional profiling of VEGF-A and VEGF-C target genes in lymphatic endothelium reveals endothelial-specific molecule-1 as a novel mediator of lymphangiogenesis
Identifieur interne : 006884 ( Main/Exploration ); précédent : 006883; suivant : 006885Transcriptional profiling of VEGF-A and VEGF-C target genes in lymphatic endothelium reveals endothelial-specific molecule-1 as a novel mediator of lymphangiogenesis
Auteurs : Jay W. Shin [Suisse] ; Reto Huggenberger [Suisse] ; Michael Detmar [Suisse]Source :
- Blood [ 0006-4971 ] ; 2008.
Abstract
Lymphatic vessel growth and activation, mediated by vascular endothelial growth factor (VEGF)–C and/or VEGF-A, have important roles in metastasis and in chronic inflammation. We aimed to comprehensively identify downstream molecular targets induced by VEGF-A or VEGF-C in lymphatic endothelium by analyzing the time-series transcriptional profile of treated human dermal lymphatic endothelial cells (LECs). We identified a number of genes, many not previously known to be involved in lymphangiogenesis, that were characterized either as early response genes, transiently induced genes, or progressively induced genes. Endothelial-specific molecule-1 (ESM-1) was one of the genes that were most potently induced by both VEGF-A and VEGF-C. Whereas ESM-1 induction by VEGF-A was mainly dependent on activation of VEGFR-2, VEGF-C–mediated induction depended on the activity of both VEGFR-2 and VEGFR-3. Incubation of LECs with ESM-1 increased the stimulatory effects of both VEGF-A and VEGF-C on LEC proliferation and migration, whereas ESM-1 alone had no effect. Importantly, VEGF-A (or VEGF-C) induction of LEC proliferation and migration were significantly inhibited by siRNA-mediated silencing of ESM-1 in vitro and in vivo. These studies reveal ESM-1 as a novel mediator of lymphangiogenesis and as a potential target for the inhibition of pathologic lymphatic vessel activation.
Url:
DOI: 10.1182/blood-2008-05-156331
PubMed: 18614759
PubMed Central: 2532805
Affiliations:
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Shin</name><affiliation wicri:level="1"><nlm:aff id="aff1">Institute of Pharmaceutical Sciences, Swiss Federal Institute of Technology, ETH Zurich, Zurich, Switzerland</nlm:aff><country xml:lang="fr">Suisse</country><wicri:regionArea>Institute of Pharmaceutical Sciences, Swiss Federal Institute of Technology, ETH Zurich, Zurich</wicri:regionArea><wicri:noRegion>Zurich</wicri:noRegion></affiliation></author><author><name sortKey="Huggenberger, Reto" sort="Huggenberger, Reto" uniqKey="Huggenberger R" first="Reto" last="Huggenberger">Reto Huggenberger</name><affiliation wicri:level="1"><nlm:aff id="aff1">Institute of Pharmaceutical Sciences, Swiss Federal Institute of Technology, ETH Zurich, Zurich, Switzerland</nlm:aff><country xml:lang="fr">Suisse</country><wicri:regionArea>Institute of Pharmaceutical Sciences, Swiss Federal Institute of Technology, ETH Zurich, Zurich</wicri:regionArea><wicri:noRegion>Zurich</wicri:noRegion></affiliation></author><author><name sortKey="Detmar, Michael" sort="Detmar, Michael" uniqKey="Detmar M" first="Michael" last="Detmar">Michael Detmar</name><affiliation wicri:level="1"><nlm:aff id="aff1">Institute of Pharmaceutical Sciences, Swiss Federal Institute of Technology, ETH Zurich, Zurich, Switzerland</nlm:aff><country xml:lang="fr">Suisse</country><wicri:regionArea>Institute of Pharmaceutical Sciences, Swiss Federal Institute of Technology, ETH Zurich, Zurich</wicri:regionArea><wicri:noRegion>Zurich</wicri:noRegion></affiliation></author></analytic><series><title level="j">Blood</title><idno type="ISSN">0006-4971</idno><idno type="eISSN">1528-0020</idno><imprint><date when="2008">2008</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en"><p>Lymphatic vessel growth and activation, mediated by vascular endothelial growth factor (VEGF)–C and/or VEGF-A, have important roles in metastasis and in chronic inflammation. We aimed to comprehensively identify downstream molecular targets induced by VEGF-A or VEGF-C in lymphatic endothelium by analyzing the time-series transcriptional profile of treated human dermal lymphatic endothelial cells (LECs). We identified a number of genes, many not previously known to be involved in lymphangiogenesis, that were characterized either as early response genes, transiently induced genes, or progressively induced genes. Endothelial-specific molecule-1 (ESM-1) was one of the genes that were most potently induced by both VEGF-A and VEGF-C. Whereas ESM-1 induction by VEGF-A was mainly dependent on activation of VEGFR-2, VEGF-C–mediated induction depended on the activity of both VEGFR-2 and VEGFR-3. Incubation of LECs with ESM-1 increased the stimulatory effects of both VEGF-A and VEGF-C on LEC proliferation and migration, whereas ESM-1 alone had no effect. Importantly, VEGF-A (or VEGF-C) induction of LEC proliferation and migration were significantly inhibited by siRNA-mediated silencing of ESM-1 in vitro and in vivo. These studies reveal ESM-1 as a novel mediator of lymphangiogenesis and as a potential target for the inhibition of pathologic lymphatic vessel activation.</p></div></front></TEI><affiliations><list><country><li>Suisse</li></country></list><tree><country name="Suisse"><noRegion><name sortKey="Shin, Jay W" sort="Shin, Jay W" uniqKey="Shin J" first="Jay W." last="Shin">Jay W. Shin</name></noRegion><name sortKey="Detmar, Michael" sort="Detmar, Michael" uniqKey="Detmar M" first="Michael" last="Detmar">Michael Detmar</name><name sortKey="Huggenberger, Reto" sort="Huggenberger, Reto" uniqKey="Huggenberger R" first="Reto" last="Huggenberger">Reto Huggenberger</name></country></tree></affiliations></record>Pour manipuler ce document sous Unix (Dilib)
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