Golding-Ochsenbein, Alexandra, Vidal, Solange, Wilmering Wetter, Barbara, Guibourdenche, Christel, Beerli, Christian, Chang, Lena, Leonhard, Sabine, Holway, Nicholas, Seuwen, Klaus and Jurisic Snijder, Giorgia (2019) S1P-S1PR1 activity controls VEGF-A signaling during lymphatic vessel development. bioRxiv. ISSN 10.1101/845396

Abstract

Sphingosine-1-phosphate (S1P), a lipid signaling molecule produced by endothelial cells, is required for development and homeostasis of blood vessels. However, its role during lymphatic vessel development is unclear. We show in murine newborns that pharmaco-logically enhanced S1P signaling increases VEGF-A-dependent LEC proliferation. In contrast, S1PR1 inhibition, mediated by the antagonist NIBR0213 or LEC-specific genet-ic deletion of S1pr1, promotes filopodia formation and vessel branching, independent of VEGF-A. To investigate the S1P and VEGF-A signaling crosstalk observed in vivo, we used LECs cultured in vitro. We demonstrate that S1P activates endogenous S1PR1 in a constitutive, autocrine manner. Importantly, S1P-S1PR1 activity was required for VEGF-A-induced LEC proliferation and strongly supported ERK1/2 activation and VEGFR-2 trafficking to the perinuclear area. In conclusion, S1P-S1PR1 signaling promotes VEGF-A-dependent LEC proliferation and limits migratory and filopodia-forming responses. Hence, S1P-S1PR1 signaling is required for balanced growth factor-induced lymphangi-ogenesis and correctly patterned lymphatic vessels during postnatal development.

Item Type:	Article
Date Deposited:	09 Dec 2019 00:45
Last Modified:	09 Dec 2019 00:45
URI:	https://oak.novartis.com/id/eprint/39503