Endothelin-1 stimulates lymphatic endothelial cells and lymphatic vessels to grow and invade

Francesca Spinella, Emirena Garrafa, Valeriana Di Castro, Laura Rosanò, Maria Rita Nicotra, Arnaldo Caruso, Pier Giorgio Natali, Anna Bagnato

Research output: Contribution to journalArticlepeer-review

Abstract

The lymphatic vasculature is essential for tissue fluid homeostasis and cancer metastasis, although the molecular mechanisms involved remain poorly characterized. Endothe- lin-1 (ET-1) axis plays a crucial role in angiogenesis and tumorigenesis. Here, we first report that ET-1 acts as a lymphangiogenic mediator. We performed in vitro and in vivo studies and show that lymphatic endothelial cells produce ET- 1, ET-3, and express the endothelin B receptor (ETBR). In these cells, ET-1 promotes proliferation, invasiveness, vascular-like structures formation, and phosphorylation of AKT and p42/44 mitogen-activated protein kinase through ETBR. In normoxic conditions, ET-1 is also able to up-regulate the expression of vascular endothelial growth factor (VEGF)-C, VEGF receptor- 3, and VEGF-A, and to stimulate hypoxia-inducible factor (HIF)-la. expression similarly to hypoxia. Moreover, HI I -1 a silencing by siBNA desensitizes VEGF-C and VEGF-A production in response to ET-1 or hypoxia, implicating HIF-1α/VEGF as downstream signaling molecules of ET-1 axis. Double immunofluorescence analysis of human lymph nodes reveals that lymphatic vessels express ETBR together with the lymphatic marker podoplanin. Furthermore, a Matrigel plug assay shows that ET-1 promotes the outgrowth of lymphatic vessels in vivo. ETBR blockade with the specific antagonist, BQ788, inhibits in vitro and in vivo ET-l-induced effects, demonstrating that ET-1 through ETBR directly regulates lymphatic vessel formation and by interacting with the HIF- 1α -dependent machinery can amplify the VEGF-mediated lymphatic vascularization. Our results suggest that ET-1 axis is indeed a new player in lymphangiogenesis and that targeting pharmacologically ETBR and related signaling cascade may be therapeutically exploited in a variety of diseases including cancer.

Original languageEnglish
Pages (from-to)2669-2676
Number of pages8
JournalCancer Research
Volume69
Issue number6
DOIs
Publication statusPublished - Mar 15 2009

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

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