title: Galectin-3 Inhibition by a Small-Molecule Inhibitor Reduces Both Pathological Corneal Neovascularization and Fibrosis.
abstract: Corneal neovascularization and scarring commonly lead to significant vision loss. This study was designed to determine whether a small-molecule inhibitor of galectin-3 can inhibit both corneal angiogenesis and fibrosis in experimental mouse models.
  
  
  
  Animal models of silver nitrate cautery and alkaline burn were used to induce mouse corneal angiogenesis and fibrosis, respectively. Corneas were treated with the galectin-3 inhibitor, 33DFTG, or vehicle alone and were processed for whole-mount immunofluorescence staining and Western blot analysis to quantify the density of blood vessels and markers of fibrosis. In addition, human umbilical vein endothelial cells (HUVECs) and primary human corneal fibroblasts were used to analyze the role of galectin-3 in the process of angiogenesis and fibrosis in vitro.
  
  
  
  Robust angiogenesis was observed in silver nitrate-cauterized corneas on day 5 post injury, and markedly increased corneal opacification was demonstrated in alkaline burn-injured corneas on days 7 and 14 post injury. Treatment with the inhibitor substantially reduced corneal angiogenesis and opacification with a concomitant decrease in α-smooth muscle actin (α-SMA) expression and distribution. In vitro studies revealed that 33DFTG inhibited VEGF-A-induced HUVEC migration and sprouting without cytotoxic effects. The addition of exogenous galectin-3 to corneal fibroblasts in culture induced the expression of fibrosis-related proteins, including α-SMA and connective tissue growth factor.
  
  
  
  Our data provide proof of concept that targeting galectin-3 by the novel, small-molecule inhibitor, 33DFTG, ameliorates pathological corneal angiogenesis as well as fibrosis. These findings suggest a potential new therapeutic strategy for treating ocular disorders related to pathological angiogenesis and fibrosis.
authors.affiliation: Program in Cell, Molecular and Developmental Biology, Sackler School of Graduate Biomedical Sciences, Tufts University, Boston, Massachusetts, United States.
authors.forename: Wei-Sheng
authors.initials: WS
authors.lastname: Chen
authors.affiliation: New England Eye Center/Department of Ophthalmology, Tufts University, Boston, Massachusetts, United States.
authors.forename: Zhiyi
authors.initials: Z
authors.lastname: Cao
authors.affiliation: Section of Microbiology Immunology and Glycobiology, Department of Laboratory Medicine, Lund University, Lund, Sweden.
authors.forename: Hakon
authors.initials: H
authors.lastname: Leffler
authors.affiliation: Centre for Analysis and Synthesis, Department of Chemistry, Lund University, Lund, Sweden.
authors.forename: Ulf J
authors.initials: UJ
authors.lastname: Nilsson
authors.affiliation: Program in Cell, Molecular and Developmental Biology, Sackler School of Graduate Biomedical Sciences, Tufts University, Boston, Massachusetts, United States 2New England Eye Center/Department of Ophthalmology, Tufts University, Boston, Massachusetts, United States.
authors.forename: Noorjahan
authors.initials: N
authors.lastname: Panjwani
mesh_terms: D020533:Angiogenesis Inhibitors / Q000494:pharmacology*; D000818:Animals; D015153:Blotting, Western; D002465:Cell Movement; D002478:Cells, Cultured; D003315:Cornea / Q000187:drug effects / Q000378:metabolism / Q000473:pathology*; D003316:Corneal Diseases / Q000473:pathology / Q000517:prevention & control; D016510:Corneal Neovascularization / Q000473:pathology / Q000517:prevention & control*; D004195:Disease Models, Animal; D005355:Fibrosis / Q000473:pathology / Q000517:prevention & control; D005434:Flow Cytometry; D037502:Galectin 3 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D053773:Transforming Growth Factor beta1 / Q000494:pharmacology
chemical_list: D020533:Angiogenesis Inhibitors; D037502:Galectin 3; D053773:Transforming Growth Factor beta1