April 2011
Volume 52, Issue 14
Free
ARVO Annual Meeting Abstract  |   April 2011
Galectin-3 Modulates Cell Surface Expression and Activation of VEGF Receptor 2
Author Affiliations & Notes
  • Kevin C. Jefferies
    Ophthalmology, Tufts University, Boston, Massachusetts
    New England Eye Center, Boston, Massachusetts
  • Anna I. Markowska
    Ophthalmology, Tufts University, Boston, Massachusetts
    New England Eye Center, Boston, Massachusetts
  • Noorjahan Panjwani
    Ophthalmology, Tufts University, Boston, Massachusetts
    New England Eye Center, Boston, Massachusetts
  • Footnotes
    Commercial Relationships  Kevin C. Jefferies, None; Anna I. Markowska, None; Noorjahan Panjwani, None
  • Footnotes
    Support  NIH: EY007088 (NP); New England Corneal Transplant Fund, Mass Lions Eye Research Fund, Research to Prevent Blindness Grant, Consortium for Functional Glycomics (GM62116).
Investigative Ophthalmology & Visual Science April 2011, Vol.52, 6407. doi:
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      Kevin C. Jefferies, Anna I. Markowska, Noorjahan Panjwani; Galectin-3 Modulates Cell Surface Expression and Activation of VEGF Receptor 2. Invest. Ophthalmol. Vis. Sci. 2011;52(14):6407.

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Abstract

Purpose: : Angiogenesis is a key factor in the pathogenesis of a number of ocular diseases including corneal graft failure, age-related macular degeneration, and diabetic retinopathy. Previous studies suggest that galectin-3, a lectin that preferentially binds N-glycans synthesized by the enzyme Mgat5, is pro-angiogenic. Since vascular endothelial growth factor A (VEGF-A) is a key mediator of angiogenesis, we postulated that galectin-3 is directly involved in VEGF-A mediated angiogenesis.

Methods: : Western blot analysis was employed to test for activation of VEGF-R2 by galectin-3 in endothelial cells. To test for an N-glycan-specific, cell surface interaction between galectin-3 and VEGF-R2, biotin-labeling and cross-linking studies were conducted in galectin-3 and Mgat5 knockdown cells, and confocal microscopy and cell surface labeling was used to test for changes in plasma membrane expression of VEGF-R2. The effect of galectin-3 on VEGF-A-mediated angiogenesis was evaluated using an in vitro, three dimensional angiogenesis assay, and its in vivo effect was evaluated using the suture model of corneal neovascularization.

Results: : We found a carbohydrate-dependent interaction between galectin-3 and VEGF-R2. Galectin-3 delays the endocytic removal of the VEGF-R2 receptor in a carbohydrate-dependent manner, as the disruption of either galectin-3 or Mgat5 reduces the cell surface localization of VEGF-R2. We also demonstrate that the addition of exogenous galectin-3 results in time-dependent phosphorylation of VEGF-R2, and that galectin-3 expression is rate-limiting for VEGF-mediated capillary sprouting, a key early indicator of angiogenesis. Finally, a 42% reduction in suture-induced neovascularization (+/-4.2%) was observed in galectin-3 null animals.

Conclusions: : The data presented here suggest that by regulating VEGF-R2 internalization and phosphorylation, galectin-3 makes a significant contribution to VEGF-A-mediated angiogenesis and corneal neovascularization.

Keywords: cornea: basic science • neovascularization • vascular endothelial growth factor 
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