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Stimulation of lymphangiogenesis via VEGFR-3 inhibits chronic skin inflammation
The role of lymphangiogenesis in inflammation has remained unclear. To investigate the role of lymphatic versus blood vasculature in chronic skin inflammation, we inhibited vascular endothelial growth factor (VEGF) receptor (VEGFR) signaling by function-blocking antibodies in the established keratin...
Autores principales: | , , , , , |
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Formato: | Texto |
Lenguaje: | English |
Publicado: |
The Rockefeller University Press
2010
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2947063/ https://www.ncbi.nlm.nih.gov/pubmed/20837699 http://dx.doi.org/10.1084/jem.20100559 |
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author | Huggenberger, Reto Ullmann, Stefan Proulx, Steven T. Pytowski, Bronislaw Alitalo, Kari Detmar, Michael |
author_facet | Huggenberger, Reto Ullmann, Stefan Proulx, Steven T. Pytowski, Bronislaw Alitalo, Kari Detmar, Michael |
author_sort | Huggenberger, Reto |
collection | PubMed |
description | The role of lymphangiogenesis in inflammation has remained unclear. To investigate the role of lymphatic versus blood vasculature in chronic skin inflammation, we inhibited vascular endothelial growth factor (VEGF) receptor (VEGFR) signaling by function-blocking antibodies in the established keratin 14 (K14)–VEGF-A transgenic (Tg) mouse model of chronic cutaneous inflammation. Although treatment with an anti–VEGFR-2 antibody inhibited skin inflammation, epidermal hyperplasia, inflammatory infiltration, and angiogenesis, systemic inhibition of VEGFR-3, surprisingly, increased inflammatory edema formation and inflammatory cell accumulation despite inhibition of lymphangiogenesis. Importantly, chronic Tg delivery of the lymphangiogenic factor VEGF-C to the skin of K14-VEGF-A mice completely inhibited development of chronic skin inflammation, epidermal hyperplasia and abnormal differentiation, and accumulation of CD8 T cells. Similar results were found after Tg delivery of mouse VEGF-D that only activates VEGFR-3 but not VEGFR-2. Moreover, intracutaneous injection of recombinant VEGF-C156S, which only activates VEGFR-3, significantly reduced inflammation. Although lymphatic drainage was inhibited in chronic skin inflammation, it was enhanced by Tg VEGF-C delivery. Together, these results reveal an unanticipated active role of lymphatic vessels in controlling chronic inflammation. Stimulation of functional lymphangiogenesis via VEGFR-3, in addition to antiangiogenic therapy, might therefore serve as a novel strategy to treat chronic inflammatory disorders of the skin and possibly also other organs. |
format | Text |
id | pubmed-2947063 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2010 |
publisher | The Rockefeller University Press |
record_format | MEDLINE/PubMed |
spelling | pubmed-29470632011-03-27 Stimulation of lymphangiogenesis via VEGFR-3 inhibits chronic skin inflammation Huggenberger, Reto Ullmann, Stefan Proulx, Steven T. Pytowski, Bronislaw Alitalo, Kari Detmar, Michael J Exp Med Article The role of lymphangiogenesis in inflammation has remained unclear. To investigate the role of lymphatic versus blood vasculature in chronic skin inflammation, we inhibited vascular endothelial growth factor (VEGF) receptor (VEGFR) signaling by function-blocking antibodies in the established keratin 14 (K14)–VEGF-A transgenic (Tg) mouse model of chronic cutaneous inflammation. Although treatment with an anti–VEGFR-2 antibody inhibited skin inflammation, epidermal hyperplasia, inflammatory infiltration, and angiogenesis, systemic inhibition of VEGFR-3, surprisingly, increased inflammatory edema formation and inflammatory cell accumulation despite inhibition of lymphangiogenesis. Importantly, chronic Tg delivery of the lymphangiogenic factor VEGF-C to the skin of K14-VEGF-A mice completely inhibited development of chronic skin inflammation, epidermal hyperplasia and abnormal differentiation, and accumulation of CD8 T cells. Similar results were found after Tg delivery of mouse VEGF-D that only activates VEGFR-3 but not VEGFR-2. Moreover, intracutaneous injection of recombinant VEGF-C156S, which only activates VEGFR-3, significantly reduced inflammation. Although lymphatic drainage was inhibited in chronic skin inflammation, it was enhanced by Tg VEGF-C delivery. Together, these results reveal an unanticipated active role of lymphatic vessels in controlling chronic inflammation. Stimulation of functional lymphangiogenesis via VEGFR-3, in addition to antiangiogenic therapy, might therefore serve as a novel strategy to treat chronic inflammatory disorders of the skin and possibly also other organs. The Rockefeller University Press 2010-09-27 /pmc/articles/PMC2947063/ /pubmed/20837699 http://dx.doi.org/10.1084/jem.20100559 Text en © 2010 Huggenberger et al. This article is distributed under the terms of an Attribution–Noncommercial–Share Alike–No Mirror Sites license for the first six months after the publication date (see http://www.rupress.org/terms). After six months it is available under a Creative Commons License (Attribution–Noncommercial–Share Alike 3.0 Unported license, as described at http://creativecommons.org/licenses/by-nc-sa/3.0/). |
spellingShingle | Article Huggenberger, Reto Ullmann, Stefan Proulx, Steven T. Pytowski, Bronislaw Alitalo, Kari Detmar, Michael Stimulation of lymphangiogenesis via VEGFR-3 inhibits chronic skin inflammation |
title | Stimulation of lymphangiogenesis via VEGFR-3 inhibits chronic skin inflammation |
title_full | Stimulation of lymphangiogenesis via VEGFR-3 inhibits chronic skin inflammation |
title_fullStr | Stimulation of lymphangiogenesis via VEGFR-3 inhibits chronic skin inflammation |
title_full_unstemmed | Stimulation of lymphangiogenesis via VEGFR-3 inhibits chronic skin inflammation |
title_short | Stimulation of lymphangiogenesis via VEGFR-3 inhibits chronic skin inflammation |
title_sort | stimulation of lymphangiogenesis via vegfr-3 inhibits chronic skin inflammation |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2947063/ https://www.ncbi.nlm.nih.gov/pubmed/20837699 http://dx.doi.org/10.1084/jem.20100559 |
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