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  • Pathological lymphangiogenesis is modulated by galectin-8-dependent crosstalk between podoplanin and integrin-associated VEGFR-3.

Pathological lymphangiogenesis is modulated by galectin-8-dependent crosstalk between podoplanin and integrin-associated VEGFR-3.

Nature communications (2016-04-14)
Wei-Sheng Chen, Zhiyi Cao, Satoshi Sugaya, Maria J Lopez, Victor G Sendra, Nora Laver, Hakon Leffler, Ulf J Nilsson, Jianxin Fu, Jianhua Song, Lijun Xia, Pedram Hamrah, Noorjahan Panjwani
ABSTRACT

Lymphangiogenesis plays a pivotal role in diverse pathological conditions. Here, we demonstrate that a carbohydrate-binding protein, galectin-8, promotes pathological lymphangiogenesis. Galectin-8 is markedly upregulated in inflamed human and mouse corneas, and galectin-8 inhibitors reduce inflammatory lymphangiogenesis. In the mouse model of corneal allogeneic transplantation, galectin-8-induced lymphangiogenesis is associated with an increased rate of corneal graft rejection. Further, in the murine model of herpes simplex virus keratitis, corneal pathology and lymphangiogenesis are ameliorated in Lgals8(-/-) mice. Mechanistically, VEGF-C-induced lymphangiogenesis is significantly reduced in the Lgals8(-/-) and Pdpn(-/-) mice; likewise, galectin-8-induced lymphangiogenesis is reduced in Pdpn(-/-) mice. Interestingly, knockdown of VEGFR-3 does not affect galectin-8-mediated lymphatic endothelial cell (LEC) sprouting. Instead, inhibiting integrins α1β1 and α5β1 curtails both galectin-8- and VEGF-C-mediated LEC sprouting. Together, this study uncovers a unique molecular mechanism of lymphangiogenesis in which galectin-8-dependent crosstalk among VEGF-C, podoplanin and integrin pathways plays a key role.

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BIO 1211 trifluoroacetate salt, ≥97% (HPLC)