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Noorjahan A Panjwani, Wei-Sheng Chen, Zhiyi Cao, Satoshi Sugaya, Hakon Leffler, Ulf J Nilsson, Lijun Xia; Pathological lymphangiogenesis is regulated by galectin-8-dependent crosstalk among VEGF-C, podoplanin and integrin pathways. Invest. Ophthalmol. Vis. Sci. 2015;56(7 ):4502.
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© ARVO (1962-2015); The Authors (2016-present)
Lymphangiogenesis (LA) plays a vital role in diverse pathological conditions including corneal graft rejection, dry eye and glaucoma. The goal of the current study was to characterize the role galectin-mediated carbohydrate recognition system in the modulation pathological LA.
Lymphatic endothelial cell (LEC) sprouting assays, corneal micropocket assays, gene knockdown and antibody blocking assays, and galectin-8 and podoplanin knockout mice were used to assess the role and the mechanism of galectin-8-mediated LA.
The study revealed that galectin-8 is a potent lymphangiogenic factor. Galectin-8 was markedly upregulated in inflamed human and mouse corneas, and inhibitors of galectin-8 reduced inflammatory LA. In corneal micropocket assays and 3D sprouting assays, galectin-8 promoted LA in a carbohydrate-dependent manner. Galectin-8 was identified as a key mediator of integrin-dependent crosstalk between VEGF-C and podoplanin lymphangiogenic pathways. Galectin-8 inhibitors reduced VEGF-C-induced LA. Conversely, exogenous galectin-8 markedly enhanced VEGF-C-induced lymphangiogenesis in a carbohydrate-dependent manner. Knockdown of podoplanin reduced not only galectin-8 but also VEGF-C-mediated LEC sprouting. Also, in corneal micropocket assays, VEGF-C-induced LA was significantly reduced in the galectin-8-/- and podoplanin-/- mice; likewise, galectin-8-induced lymphangiogenesis was reduced in podoplanin-/- mice. Interestingly, knockdown of VEGFR-3 did not affect galectin-8-mediated LEC sprouting. Instead, inhibiting integrins α1β1 and α5β1 curtailed both galectin-8- and VEGF-C-mediated LEC sprouting. Additionally, podoplanin knockdown in LECs interfered with integrin activation. Immunoprecipitation assays further confirmed galectin-8-dependent interactions between podoplanin and integrins α5 and β1.
This study has uncovered a unique lymphangiogenic pathway in which galectin-8-mediated interactions between PDPN and integrins α1β1/α5β1 play a key role.
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