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

• DOI: 10.1172/jci.insight.137652
• Publication Date: 2020-06-16T16:04:50Z
• 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 Wythe; Constantinos M. M...; Timothy Hla; R. Sathish Sriniv...
• Keywords: Lymphangiogenesis; S1PR1; Lymphatic Endothelium; Filopodia; Lymphatic vessel

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