September 2016
Volume 57, Issue 12
Open Access
ARVO Annual Meeting Abstract  |   September 2016
Pathological lymphangiogenesis is regulated by galectin-8-dependent crosstalk among VEGF-C, podoplanin and integrin pathways
Author Affiliations & Notes
  • Wei-Sheng Chen
    Ophthalmology, Tufts University, Boston, Massachusetts, United States
  • Zhiyi Cao
    Ophthalmology, Tufts University, Boston, Massachusetts, United States
  • Satoshi Sugaya
    Ophthalmology, Tufts University, Boston, Massachusetts, United States
  • Maria Jose Lopez
    Ophthalmology, Tufts University, Boston, Massachusetts, United States
  • Victor Sendra
    Ophthalmology, Tufts University, Boston, Massachusetts, United States
  • Nora V Laver
    Ophthalmology, Tufts University, Boston, Massachusetts, United States
  • Pedram Hamrah
    Ophthalmology, Tufts University, Boston, Massachusetts, United States
  • Noorjahan A Panjwani
    Ophthalmology, Tufts University, Boston, Massachusetts, United States
  • Footnotes
    Commercial Relationships   Wei-Sheng Chen, None; Zhiyi Cao, None; Satoshi Sugaya, None; Maria Lopez, None; Victor Sendra, None; Nora Laver, None; Pedram Hamrah, None; Noorjahan Panjwani, None
  • Footnotes
    Support  R01 EY007088
Investigative Ophthalmology & Visual Science September 2016, Vol.57, No Pagination Specified. doi:
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      Wei-Sheng Chen, Zhiyi Cao, Satoshi Sugaya, Maria Jose Lopez, Victor Sendra, Nora V Laver, Pedram Hamrah, Noorjahan A Panjwani; Pathological lymphangiogenesis is regulated by galectin-8-dependent crosstalk among VEGF-C, podoplanin and integrin pathways. Invest. Ophthalmol. Vis. Sci. 201657(12):.

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      © 2017 Association for Research in Vision and Ophthalmology.

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Abstract

Purpose : 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.

Methods : 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.

Results : We demonstrate for the first time that a carbohydrate-binding protein, 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. In the mouse model of corneal allogeneic transplantation, galectin-8-induced lymphangiogenesis was associated with an increased rate of corneal graft rejection. Further, utilizing the murine model of herpes simplex virus keratitis, we demonstrated that corneal pathology and LA were ameliorated in galectin-8 knockout mice. Mechanistic studies revealed that galectin-8 inhibitors reduce VEGF-C-induced LA. Conversely, exogenous galectin-8 markedly enhanced VEGF-C-induced LA in a carbohydrate-dependent manner. Knockdown of podoplanin attenuated 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 LA 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.

Conclusions : This study has uncovered a unique lymphangiogenic pathway in which galectin-8-mediated interactions between PDPN and integrins α1β1/α5β1 play a key role.

This is an abstract that was submitted for the 2016 ARVO Annual Meeting, held in Seattle, Wash., May 1-5, 2016.

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