Inflammation induces lymphangiogenesis through up-regulation of VEGFR-3 mediated by NF- (cid:1) B and Prox1

Theconceptofinflammation-inducedlym-phangiogenesis (ie, formation of new lymphatic vessels) has long been recog-nized, 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- (cid:1) B) family; how-ever, the role of NF- (cid:1) B in regulation of lymphatic-specific genes has not been defined. Here, we identified VEGFR-3 and Prox1asdownstreamtargetsoftheNF- (cid:1) B pathway. In vivo time-course analysis of inflammation-induced lymphangiogenesis showed activation of NF- (cid:1) B followed by sequential up-regulation of Prox1 and VEGFR-3 that preceded lymphangiogenesis by 4 and 2 days, respectively.Activa-tion of NF- (cid:1) B 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- (cid:1) B to control VEGFR-3 expression. Collectively, our findings suggest that induction of the NF- (cid:1) B pathway by inflammatory stimuli activates Prox1, and both NF- (cid:1) B 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. (Blood. 2010;115: 418-429)

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