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

YAP and TAZ maintain PROX1 expression in the developing lymphatic and lymphovenous valves in response to VEGF-C signaling

“…S3E,F " type="url"/> ). This is likely due to the blood vascular defects caused by Lyve1-Cre expression in the blood vessels of the gut, as reported previously ( Dellinger et al, 2013 ; Geng et al, 2020 ). Consequently, we are unable to conclude whether the defects in the mesenteric lymphatic vessels of Yap/Taz LECKO embryos are due to YAP and TAZ activity in LECs or to blood vascular endothelial cells.…”

“…Consequently, we are unable to conclude whether the defects in the mesenteric lymphatic vessels of Yap/Taz LECKO embryos are due to YAP and TAZ activity in LECs or to blood vascular endothelial cells. Nevertheless, Lyve1-Cre is specific to dermal lymphatic vasculature ( Dellinger et al, 2013 ; Geng et al, 2020 ). Hence, based on our findings we conclude that YAP and TAZ are not required for the differentiation of valvular endothelial cells (LVVs and LVs).…”

“…LVs develop within the collecting lymphatic vessels ( Bazigou et al, 2009 ; Norrmén et al, 2009 ; Petrova et al, 2004 ). Maturation of lymphatic plexus and the formation of valves are regulated by various signaling molecules such as VEGF-C, neuropilin 2, Wnt/β-catenin, S1PR1, BMP9, ephrin B2, EPH-B4, plexins and semaphorins ( Bouvrée et al, 2012 ; Cha et al, 2016 , 2018 ; Geng et al, 2020 ; Jurisic et al, 2012 ; Levet et al, 2013 ; Liu et al, 2014 , 2016 ; Makinen et al, 2005 ; Martin-Almedina et al, 2016 ; Nurmi et al, 2015 ; Yuan et al, 2002 ). Shear stress generated by lymph flow also plays a deterministic role in lymphatic vascular morphogenesis ( Cha et al, 2016 , 2018 ; Choi et al, 2019 , 2017a , b ; Geng et al, 2020 ; Liu et al, 2014 ; Sabine et al, 2012 ; Sweet et al, 2015 ; Wang et al, 2016 ).…”

Molecular Mechanisms Controlling Lymphatic Endothelial Junction Integrity

“…As LPAR1 signaling controls RhoA/ROCK-mediated cytoskeletal dynamics (Ridley, 2001 ; Hall, 2012 ; Knipe et al, 2015 ), LPA treatment induces stress fiber formation, increased phosphorylation of MLC, and the formation of punctate, intracellular gaps in VE-cadherin-stained cell junctions in human umbilical vein endothelial cells (HUVECs), whereas S1PR1 activation stimulates continuous, zipper-like junctions with cortical F-actin formation. Moreover, it was recently shown that S1PR1 signaling suppresses RhoA GTPase activation in cultured LECs, whereas its blockade results in the formation of discontinuous LEC junctions, which is rescued by ROCK inhibitor Y-27632 (Geng et al, 2020 ) ( Figure 2C ). In contrast to activation of LPAR1 or S1PR1 individually in HUVECs, combined activation of both LPAR1 and S1PR1 results in a hybrid of continuous cell junctions interspersed with punctate VE-cadherin+ structures at the termini of actin-rich stress fibers.…”

“…Furthermore, antibody mediated inhibition of EphrinB2 resulted in the formation of discontinuous cell junctions, which was accompanied by reduced junctional CLDN5 distribution and stimulation of aberrant actin stress fiber formation (Frye et al, 2020 ). In contrast, siRNA-mediated knockdown or chemical inhibition of S1PR1 in HDLECs was shown to enhance RhoA GTPase activation, which also resulted in the formation of discontinuous cell junctions and reduced junctional CLDN5 distribution (Geng et al, 2020 ). In both instances, pretreatment of HDLECs with Y-27632 was able to rescue the impaired phenotype induced by inhibition of either EphrinB2/EphB4 or S1PR1 signaling.…”