S1PR1 regulates the quiescence of lymphatic vessels by inhibiting laminar shear stress–dependent VEGF-C signaling
Xin Geng, … , Timothy Hla, R. Sathish Srinivasan
Xin Geng, … , Timothy Hla, R. Sathish Srinivasan
Published June 16, 2020
Citation Information: JCI Insight. 2020;5(14):e137652. https://doi.org/10.1172/jci.insight.137652.
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Research Article Development Vascular biology

S1PR1 regulates the quiescence of lymphatic vessels by inhibiting laminar shear stress–dependent VEGF-C signaling

Abstract

During the growth of lymphatic vessels (lymphangiogenesis), lymphatic endothelial cells (LECs) at the growing front sprout by forming filopodia. Those tip cells are not exposed to circulating lymph, as they are not lumenized. In contrast, LECs that trail the growing front are exposed to shear stress, become quiescent, and remodel into stable vessels. The mechanisms that coordinate the opposed activities of lymphatic sprouting and maturation remain poorly understood. Here, we show that the canonical tip cell marker Delta-like 4 (DLL4) promotes sprouting lymphangiogenesis by enhancing VEGF-C/VEGF receptor 3 (VEGFR3) signaling. However, in lumenized lymphatic vessels, laminar shear stress (LSS) inhibits the expression of DLL4, as well as additional tip cell markers. Paradoxically, LSS also upregulates VEGF-C/VEGFR3 signaling in LECs, but sphingosine 1-phosphate receptor 1 (S1PR1) activity antagonizes LSS-mediated VEGF-C signaling to promote lymphatic vascular quiescence. Correspondingly, S1pr1 loss in LECs induced lymphatic vascular hypersprouting and hyperbranching, which could be rescued by reducing Vegfr3 gene dosage in vivo. In addition, S1PR1 regulates lymphatic vessel maturation by inhibiting RhoA activity to promote membrane localization of the tight junction molecule claudin-5. Our findings suggest a potentially new paradigm in which LSS induces quiescence and promotes the survival of LECs by downregulating DLL4 and enhancing VEGF-C signaling, respectively. S1PR1 dampens LSS/VEGF-C signaling, thereby preventing sprouting from quiescent lymphatic vessels. These results also highlight the distinct roles that S1PR1 and DLL4 play in LECs when compared with their known roles in the blood vasculature.

Authors

Xin Geng, Keisuke Yanagida, Racheal G. Akwii, Dongwon Choi, Lijuan Chen, YenChun Ho, Boksik Cha, Md. Riaj Mahamud, Karen Berman de Ruiz, Hirotake Ichise, Hong Chen, Joshua D. Wythe, Constantinos M. Mikelis, Timothy Hla, R. Sathish Srinivasan

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Figure 7

Model for the crosstalk between LSS, S1PR1, and VEGF-C signaling during lymphatic vascular patterning.

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Model for the crosstalk between LSS, S1PR1, and VEGF-C signaling during ...
(A) LSS inhibits the expression of molecules such as DLL4, ANGPT2, ADM, and ESM1, thereby limiting their expression to tip cells (i). LSS enhances VEGF-C signaling to promote the survival of quiescent LECs (ii). S1PR1 functions as a buffer that prevents the hyperactivation of LSS/VEGF-C signaling to prevent the sprouting of lymphatic vessels (ii). Lymphatic vessels that are exposed to a low dose of VEGF-C with little or no lymph flow regress due to reduced LSS/VEGF-C signaling (iii). (B) In the absence of S1PR1, VEGF-C signaling is hyperactive in the posterior lymphatic plexus, which results in an excessive number of sprouts and branches (iv). In addition to modulating LSS/VEGF-C signaling, S1PR1 inhibits RhoA activity to regulate the cytoskeleton and maintain claudin-5 expression (green vessels). Consequently, mice lacking S1PR1 have immature cell junctions (yellow vessels).