Both Autocrine Signaling and Paracrine Signaling of HB-EGF Enhance Ocular Neovascularization

Arterioscler Thromb Vasc Biol. 2018 Jan;38(1):174-185. doi: 10.1161/ATVBAHA.117.310337. Epub 2017 Nov 30.

Abstract

Objective: The incidence of blindness is increasing because of the increase in abnormal ocular neovascularization. Anti-VEGF (vascular endothelial growth factor) therapies have led to good results, although they are not a cure for the blindness. The purpose of this study was to determine what role HB-EGF (heparin-binding epidermal growth factor-like growth factor) plays in ocular angiogenesis.

Approach and results: We examined the role played by HB-EGF in ocular neovascularization in 2 animal models of neovascularization: laser-induced choroidal neovascularization (CNV) and oxygen-induced retinopathy. We also studied human retinal microvascular endothelial cells in culture. Our results showed that the neovascularization was decreased in both the CNV and oxygen-induced retinopathy models in HB-EGF conditional knockout mice compared with that in wild-type mice. Moreover, the expressions of HB-EGF and VEGF were increased after laser-induced CNV and oxygen-induced retinopathy, and their expression sites were located around the neovascular areas. Exposure of human retinal microvascular endothelial cells to HB-EGF and VEGF increased their proliferation and migration, and CRM-197 (cross-reactive material-197), an HB-EGF inhibitor, decreased the HB-EGF-induced and VEGF-induced cell proliferation and migration. VEGF increased the expression of HB-EGF mRNA. VEGF-dependent activation of EGFR (epidermal growth factor receptor)/ERK1/2 (extracellular signal-regulated kinase 1/2) signaling and cell proliferation of endothelial cells required stimulation of the ADAM17 (a disintegrin and metalloprotease) and ADAM12. CRM-197 decreased the grades of the fluorescein angiograms and size of the CNV areas in marmoset monkeys.

Conclusions: These findings suggest that HB-EGF plays an important role in the development of CNV. Therefore, further investigations of HB-EGF are needed as a potential therapeutic target in the treatment of exudative age-related macular degeneration.

Keywords: endothelial cell; heparin-binding EGF-like growth factor; macular degeneration; mice; retina; vascular diseases.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • ADAM12 Protein / genetics
  • ADAM12 Protein / metabolism
  • ADAM17 Protein / genetics
  • ADAM17 Protein / metabolism
  • Angiogenesis Inhibitors / pharmacology
  • Animals
  • Autocrine Communication* / drug effects
  • Bacterial Proteins / pharmacology
  • Callithrix
  • Cell Movement
  • Cell Proliferation
  • Cells, Cultured
  • Choroidal Neovascularization / genetics
  • Choroidal Neovascularization / metabolism*
  • Choroidal Neovascularization / pathology
  • Choroidal Neovascularization / prevention & control
  • Disease Models, Animal
  • Endothelial Cells / metabolism
  • Endothelial Cells / pathology
  • Extracellular Signal-Regulated MAP Kinases / metabolism
  • Heparin-binding EGF-like Growth Factor / deficiency
  • Heparin-binding EGF-like Growth Factor / genetics
  • Heparin-binding EGF-like Growth Factor / metabolism*
  • Humans
  • Mice, Knockout
  • Neovascularization, Pathologic*
  • Paracrine Communication* / drug effects
  • Retinal Neovascularization / genetics
  • Retinal Neovascularization / metabolism*
  • Retinal Neovascularization / pathology
  • Retinal Neovascularization / prevention & control
  • Retinal Vessels / drug effects
  • Retinal Vessels / metabolism*
  • Retinal Vessels / pathology
  • Signal Transduction
  • Vascular Endothelial Growth Factor A / genetics
  • Vascular Endothelial Growth Factor A / metabolism

Substances

  • Angiogenesis Inhibitors
  • Bacterial Proteins
  • Heparin-binding EGF-like Growth Factor
  • Vascular Endothelial Growth Factor A
  • vascular endothelial growth factor A, mouse
  • CRM197 (non-toxic variant of diphtheria toxin)
  • Extracellular Signal-Regulated MAP Kinases
  • ADAM12 Protein
  • ADAM12 protein, human
  • ADAM17 Protein
  • ADAM17 protein, human