Inflammation induces lymphangiogenesis through up-regulation of VEGFR-3 mediated by NF-kappaB and Prox1

The concept of inflammation-induced lymphangiogenesis (ie, formation of new lymphatic vessels) has long been recognized, but the molecular mechanisms remained largely unknown. The 2 primary mediators of lymphangiogenesis are vascular endothelial growth factor receptor-3 (VEGFR-3) and Prox1. The key...

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Bibliographic Details
Published in:Blood 2010-01, Vol.115 (2), p.418-429
Main Authors: Flister, Michael J, Wilber, Andrew, Hall, Kelly L, Iwata, Caname, Miyazono, Kohei, Nisato, Riccardo E, Pepper, Michael S, Zawieja, David C, Ran, Sophia
Format: Article
Language:English
Subjects:
Animals
Cell Line
Cell Movement - genetics
Cell Proliferation
Endothelial Cells - metabolism
Female
Homeodomain Proteins - genetics
Homeodomain Proteins - metabolism
Humans
Inflammation - genetics
Inflammation - metabolism
Mice
Mice, Inbred BALB C
Neovascularization, Physiologic
NF-kappa B p50 Subunit - genetics
NF-kappa B p50 Subunit - metabolism
Promoter Regions, Genetic - genetics
Rats
Time Factors
Transcription, Genetic
Tumor Suppressor Proteins - genetics
Tumor Suppressor Proteins - metabolism
Up-Regulation
Vascular Endothelial Growth Factor C - genetics
Vascular Endothelial Growth Factor C - metabolism
Vascular Endothelial Growth Factor D - genetics
Vascular Endothelial Growth Factor D - metabolism
Vascular Endothelial Growth Factor Receptor-3 - genetics
Vascular Endothelial Growth Factor Receptor-3 - metabolism
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Summary:The concept of inflammation-induced lymphangiogenesis (ie, formation of new lymphatic vessels) has long been recognized, but the molecular mechanisms remained largely unknown. The 2 primary mediators of lymphangiogenesis are vascular endothelial growth factor receptor-3 (VEGFR-3) and Prox1. The key factors that regulate inflammation-induced transcription are members of the nuclear factor-kappaB (NF-kappaB) family; however, the role of NF-kappaB in regulation of lymphatic-specific genes has not been defined. Here, we identified VEGFR-3 and Prox1 as downstream targets of the NF-kappaB pathway. In vivo time-course analysis of inflammation-induced lymphangiogenesis showed activation of NF-kappaB followed by sequential up-regulation of Prox1 and VEGFR-3 that preceded lymphangiogenesis by 4 and 2 days, respectively. Activation of NF-kappaB by inflammatory stimuli also elevated Prox1 and VEGFR-3 expression in cultured lymphatic endothelial cells, resulting in increased proliferation and migration. We also show that Prox1 synergizes with the p50 of NF-kappaB to control VEGFR-3 expression. Collectively, our findings suggest that induction of the NF-kappaB pathway by inflammatory stimuli activates Prox1, and both NF-kappaB and Prox1 activate the VEGFR-3 promoter leading to increased receptor expression in lymphatic endothelial cells. This, in turn, enhances the responsiveness of preexisting lymphatic endothelium to VEGFR-3 binding factors, VEGF-C and VEGF-D, ultimately resulting in robust lymphangiogenesis.
ISSN:1528-0020
DOI:10.1182/blood-2008-12-196840