Inflammation induces lymphangiogenesis through up-regulation of VEGFR-3 mediated by NF-κB and Prox1
- DOI: 10.1182/blood-2008-12-196840
- PubMed: 19901262
Abstract
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-κB) family; however, the role of NF-κB in regulation of lymphatic-specific genes has not been defined. Here, we identified VEGFR-3 and Prox1 as downstream targets of the NF-κB pathway. In vivo time-course analysis of inflammation-induced lymphangiogenesis showed activation of NF-κB followed by sequential up-regulation of Prox1 and VEGFR-3 that preceded lymphangiogenesis by 4 and 2 days, respectively. Activation of NF-κB 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-κB to control VEGFR-3 expression. Collectively, our findings suggest that induction of the NF-κB pathway by inflammatory stimuli activates Prox1, and both NF-κB 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-supplied keywords
Inflammation induces lymphangiogenesis through up-regulation of VEGFR-3 mediated by NF-κB and Prox1
1
Inflammation induces lymphangiogenesis through upregulation of VEGFR-3 mediated by
NF- B and Prox1
Running title: NF- B and Prox1 control VEGFR-3 expression
Michael J. Flister1, Andrew Wilber1,2, Kelly L. Hall1, Caname Iwata3, Kohei Miyazono3, Riccardo
E. Nisato4, Michael S. Pepper5, David C. Zawieja6 and Sophia Ran1
1Department of Medical Microbiology, Immunology, and Cell Biology and 2Department of
Surgery, Southern Illinois University School of Medicine, Springfield, IL, USA; 3Department of
Molecular Pathology, Graduate School of Medicine, University of Tokyo, Tokyo, Japan.
4Department of Cell Physiology and Metabolism, University Medical Center, Geneva,
Switzerland; 5Netcare Institute of Cellular and Molecular Medicine, Pretoria, South Africa; and
6Department of Systems Biology and Translational Medicine, Cardiovascular Research Institute,
Texas A & M Health Science Center, College Station, TX, USA.
Corresponding Author: Sophia Ran, Department of Medical Microbiology, Immunology and
Cell Biology, Southern Illinois University School of Medicine, 801 N. Rutledge, Springfield, IL,
62794-9626, USA. Phone: (217) 545-7026; Fax: (217) 545-7333; E-mail: sran@siumed.edu
Scientific section designation: VASCULAR BIOLOGY
Keywords: Lymphangiogenesis, VEGFR-3, Nuclear Factor-kappaB, transcriptional regulation,
inflammation
Abbreviations: BECs, blood endothelial cells; CDS, coding DNA sequence; Ct, Cycle threshold;
HRP, horseradish peroxidase; i.p., intraperitoneally; i.v., intravenously; LECs, lymphatic
Blood First Edition Paper, prepublished online November 9, 2009; DOI 10.1182/blood-2008-12-196840
Copyright © 2009 American Society of Hematology
2
endothelial cells; LVD, lymphatic vessel density; NF- B, Nuclear Factor-kappaB; PGK,
phosphoglycerate kinase; RLU, relative light units; VEGF-A, VEGF-C and VEGF-D, vascular
endothelial growth factor-A, -C and -D; VEGFR-3, vascular endothelial growth factor receptor-3;
UBC, ubiquitin C.
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