WNT7A/B promote choroidal neovascularization

Exp Eye Res. 2018 Sep;174:107-112. doi: 10.1016/j.exer.2018.05.033. Epub 2018 Jun 1.

Abstract

Perturbations in WNT signaling are associated with congenital eye disorders, including familial exudative vitreoretinopathy and Norrie disease. More recently, activation of the WNT pathway has also been shown to be associated with age-related macular degeneration (AMD). In this study, we identified that in choroidal neovascular membranes from AMD patients, β-catenin is activated specifically in the vascular endothelium, suggesting that WNT promotes pathologic angiogenesis by directly affecting vascular endothelial cells. WNT7B has been shown to be important during eye development for regression of the fetal hyaloid vasculature. However, it has not yet been established whether WNT7A and/or WNT7B are involved in neovascular AMD pathogenesis. Here, we show that WNT7A and WNT7B increase the proliferation of human dermal microvascular endothelial cells in a dose-dependent manner. Both WNT7A and WNT7B also stimulated vascular sprouting from mouse choroidal explants in vitro. To evaluate in vivo relevance, we generated mice systemically deficient in Wnt7a and/or Wnt7b. Genetic deletion of both Wnt7a and Wnt7b decreased the severity of laser injury-induced choroidal neovascularization (CNV), while individual deletion of either Wnt7a or Wnt7b did not have a significant effect on CNV, suggesting that WNT7A and WNT7B have redundant pro-angiogenic roles in vivo. Cumulatively, these findings identify specific WNT isoforms that may play a pathologic role in CNV as observed in patients with neovascular AMD. Although the source of increased WNT7A and/or WNT7B in CNV requires further investigation, WNT signaling may be a potential target for therapeutic intervention if these results are demonstrated to be relevant in human disease.

Keywords: Age-related macular degeneration; Angiogenesis; Choroidal neovascularization; WNT7A; WNT7B; β-catenin.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Angiogenesis Inhibitors / metabolism
  • Animals
  • Cell Proliferation / physiology
  • Choroidal Neovascularization / metabolism*
  • Choroidal Neovascularization / pathology
  • Endothelial Cells / pathology
  • Humans
  • Male
  • Mice
  • Signal Transduction / physiology
  • Wnt Proteins / physiology*
  • beta Catenin / metabolism

Substances

  • Angiogenesis Inhibitors
  • WNT7A protein, human
  • WNT7B protein, human
  • Wnt Proteins
  • beta Catenin