Inflammation induces lymphangiogenesis through up-regulation of VEGFR-3 mediated by NF-kappaB and Prox1. Blood 2010 Jan 14;115(2):418-29
Date
11/11/2009Pubmed ID
19901262Pubmed Central ID
PMC2808162DOI
10.1182/blood-2008-12-196840Scopus ID
2-s2.0-75649083174 (requires institutional sign-in at Scopus site) 189 CitationsAbstract
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.
Author List
Flister MJ, Wilber A, Hall KL, Iwata C, Miyazono K, Nisato RE, Pepper MS, Zawieja DC, Ran SMESH terms used to index this publication - Major topics in bold
AnimalsCell Line
Cell Movement
Cell Proliferation
Endothelial Cells
Female
Homeodomain Proteins
Humans
Inflammation
Mice
Mice, Inbred BALB C
NF-kappa B p50 Subunit
Neovascularization, Physiologic
Promoter Regions, Genetic
Rats
Time Factors
Transcription, Genetic
Tumor Suppressor Proteins
Up-Regulation
Vascular Endothelial Growth Factor C
Vascular Endothelial Growth Factor D
Vascular Endothelial Growth Factor Receptor-3
