Table 1.
Effects of mechanistic manipulations on button junctions in lymphatics
| Mechanistic manipulation | Effect on buttons | References |
|---|---|---|
| Angiopoietin-2 (ANGPT2) | Necessary for button formation in initial lymphatics | Zheng et al. 2014 |
| Calcitonin receptor–like receptor (CALCR1) | Adrenomedullin receptor upstream of DLL4; lymphatic endothelial cell-specific Calcr1 mutations result in conversion of buttons to zippers, reduced lipid uptake, and intestinal lymphangiectasia | Davis et al. 2017, 2019 |
| CD36 | Lymphatic endothelial cell-specific Cd36 deletion disrupts button junctions in lacteals and collecting lymphatics in intestine and mesentery and reduced uptake of chylomicrons | Cifarelli et al. 2021 |
| Dexamethasone | Promotes conversion of zippers to buttons during development and in inflammation | Yao et al. 2010 |
| Delta-like4 (DLL4) Notch signaling | Necessary for button formation in lacteals, signaling downstream of VEGFR2 and VEGFR3, supports lacteal regeneration | Bernier-Latmani et al. 2015 |
| EphrinB2/EphB4 signaling | Necessary for stabilization of lymphatic junctions, regulates claudin-5 expression in lymphatic endothelial cells | Frye et al. 2020 |
| Gut microbiome | Promotes VEGF-C production and button formation in lacteals, antibiotic depletion of gut bacteria results in conversion of buttons to zippers in lacteals | Suh et al. 2019 |
| Inflammation | Promotes zipper formation in lymphatic sprouts in mouse airways after infection by Mycoplasma pulmonis | Baluk et al. 2007; Yao et al. 2012 |
| LYVE1 | Lyve1 deletion has no apparent effect on lymphatic junctions or fluid drainage but reduces leukocyte transit and amplifies chronic inflammation | Gale et al. 2007; Vieira et al. 2018 |
| Mechanical stretch | Promotes VEGF-C production and button formation in lacteals | Hong et al. 2020 |
| Neuropilin1 (NRP1) | Deletion of Vegfr1 and Nrp1 together promotes VEGF-A/VEGFR2 signaling and conversion of buttons to zippers in lacteals, reduces chylomicron uptake | Zhang et al. 2018 |
| PECAM1 | Deletion of Pecam1 has no apparent effect on button junctions or leukocyte entry into initial lymphatics | Baluk et al. 2007; Wang et al. 2016 |
| RhoA/ROCK signaling | Necessary for junction formation in lacteals and for secondary valves in collecting lymphatics, ROCK inhibition by Y-27632 promotes conversion of buttons to zippers | Zhang et al. 2018; Norden and Kume 2021 |
| S1P/S1PR1 signaling | S1PR1 regulates lymphatic quiescence by inhibiting VEGF-C signaling induced by shear stress, regulates claudin-5 expression | Pham et al. 2010; Geng et al. 2020 |
| VE-cadherin (cadherin-5, CDH5) | Anti-VE-cadherin antibody promotes rapid dissolution of button junctions, postnatal Cdh5 deletion has pronounced effects on lacteals and limited effect on skin lymphatics | Baluk et al. 2007; Hägerling et al. 2018 |
| VEGF-A/VEGFR2 signaling | VEGF-A signaling through VEGFR2 in lacteals results in button conversion to zippers and reduces chylomicron uptake, inhibition of VEGFR2 by DC101 antibody promotes button formation | Zhang et al. 2018 |
| VEGFR1 | Combined deletion of Vegfr1 and Nrp1 promotes VEGF-A/VEGFR2 signaling and results in button conversion to zipper junctions in lacteals, reduces chylomicron uptake | Zhang et al. 2018 |
| VEGF-C/VEGFR3 signaling | Promotes button formation in lacteals | Nurmi et al. 2015; Hong et al. 2020 |
| YAP/TAZ signaling | Upstream of Vegfc in maintenance of buttons in lacteals, Lats1/2 deletion activates YAP/TAZ signaling and reduces buttons, YAP/TAZ signaling balance needed to maintain button integrity | Cho et al. 2019; Hong et al. 2020 |