Ets family members induce lymphangiogenesis through physical and functional interaction with Prox1

Yasuhiro Yoshimatsu,Hajime Mihira,Keiko Yuki,Takashi Minami,Taichi Itoh,Tetsuro Watabe,Junichi Suehiro,Tomoko Yamazaki,Tatsuhiko Kodama,Caname Iwata,Kohei Miyazono,Yasuyuki Morishita,Masato Morikawa,Kaori Harada

doi:10.1242/jcs.083998

Abstract

Prox1 plays pivotal roles during embryonic lymphatic development and maintenance of adult lymphatic systems by modulating the expression of various lymphatic endothelial cell (LEC) markers, such as vascular endothelial growth factor receptor 3 (VEGFR3). However, the molecular mechanisms by which Prox1 transactivates its target genes remain largely unknown. Here, we identified Ets-2 as a candidate molecule that regulates the functions of Prox1. Whereas Ets-2 has been implicated in angiogenesis, its roles during lymphangiogenesis have not yet been elucidated. We found that endogenous Ets-2 interacts with Prox1 in LECs. Using an in vivo model of chronic aseptic peritonitis, we found that Ets-2 enhanced inflammatory lymphangiogenesis, whereas a dominant-negative mutant of Ets-1 suppressed it. Ets-2 also enhanced endothelial migration towards VEGF-C through induction of expression of VEGFR3 in collaboration with Prox1. Furthermore, we found that both Prox1 and Ets-2 bind to the VEGFR3 promoter in intact chromatin. These findings suggest that Ets family members function as transcriptional cofactors that enhance Prox1-induced lymphangiogenesis.

Highlights

The vascular system comprises blood vascular and lymphatic networks and plays important roles in the maintenance of tissue fluid homeostasis (Saharinen and Petrova, 2004)
We found that both Prox1 and Ets-2 bind to the vascular endothelial growth factor receptor 3 (VEGFR3) promoter in intact chromatin
These findings suggest that Ets family members function as transcriptional cofactors that enhance Prox1-induced lymphangiogenesis

Summary

Introduction

The vascular system comprises blood vascular and lymphatic networks and plays important roles in the maintenance of tissue fluid homeostasis (Saharinen and Petrova, 2004). Recent attempts to elucidate transcriptional controls exercized during endothelial cell development in a genome-wide fashion have identified potential relationships between transcription factors and their direct target genes in endothelial cells (Carlsson and Mahlapuu, 2002; Hollenhorst et al, 2007; De Val and Black, 2009). These studies have identified Ets family members as transcription factors that play important roles in multiple steps in the formation of vascular networks. These results suggest that Ets-1 and Ets-2 play important and distinct roles in angiogenesis

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