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Vascular endothelial growth factor-B gene transfer exacerbates retinal and choroidal neovascularization and vasopermeability without promoting inflammation.

AbstractPURPOSE:
The role of vascular endothelial growth factor (VEGF)-B in the eye is poorly understood. The present study was conducted to evaluate the effect of overexpression of VEGF-B via adeno-associated virus (AAV) gene transfer on ocular angiogenesis, inflammation, and the blood-retinal barrier (BRB).
METHODS:
Three recombinant AAV vectors were prepared, expressing the 167 (AAV-VEGF-B167) or 186 amino acid isoform (AAV-VEGF-B186) of VEGF-B or the green fluorescent protein (GFP) reporter gene (AAV-GFP). Approximately 1 x 10⁹ viral genome copies of AAV-VEGF-B167, AAV-VEGF-B186, or AAV-GFP were intraocularly injected. The efficacy of the gene transfer was assessed by directly observing GFP, by immunohistochemistry, or by real-time PCR. A leukostasis assay using fluorescein isothiocyanate-conjugated Concanavalin A was used to evaluate inflammation. The BRB was assessed using a quantitative assay with ³H-mannitol as a tracer. Retinal neovascularization (NV) was assessed at postnatal day 17 in oxygen-induced ischemic retinopathy after intravitreal injection of AAV-VEGF-B in left eyes and AAV-GFP in right eyes at postnatal day 7. Two weeks after injection of AAV vectors, choroidal NV was generated by laser photocoagulation and assessed 2 weeks later.
RESULTS:
GFP expression was clearly demonstrated, primarily in the retinal pigment epithelium (RPE) and outer retina, 1-6 weeks after delivery. mRNA expression levels of VEGF-B167 and VEGF-B186 were 5.8 and 12 fold higher in the AAV-VEGF-B167- and AAV-VEGF-B186-treated groups, respectively. There was no evidence of an inflammatory response or vessel abnormality following injection of the vectors in normal mice; however, VEGF-B increased retinal and choroidal neovascularization. AAV-VEGF-B186, but not AAV-VEGF-B167, enhanced retinal vascular permeability.
CONCLUSIONS:
VEGF-B overexpression promoted pathological retinal and choroidal NV and BRB breakdown without causing inflammation, which is associated with the progression of diabetic retinopathy and age-related macular degeneration, showing that these complications are not dependent on inflammation. VEGF-B targeting could benefit antiangiogenic therapy.
AuthorsXiufeng Zhong, Hu Huang, Jikui Shen, Serena Zacchigna, Lorena Zentilin, Mauro Giacca, Stanley A Vinores
JournalMolecular vision (Mol Vis) Vol. 17 Pg. 492-507 (Feb 17 2011) ISSN: 1090-0535 [Electronic] United States
PMID21364963 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
Chemical References
  • Vascular Endothelial Growth Factor B
  • Green Fluorescent Proteins
  • Oxygen
Topics
  • Animals
  • Capillary Permeability (physiology)
  • Choroidal Neovascularization (complications, genetics, physiopathology)
  • Dependovirus (genetics)
  • Gene Transfer Techniques
  • Genetic Vectors (genetics)
  • Green Fluorescent Proteins (metabolism)
  • Inflammation (complications, physiopathology)
  • Ischemia (complications, physiopathology)
  • Mice
  • Mice, Inbred C57BL
  • Oxygen
  • Recombination, Genetic (genetics)
  • Retina (pathology, physiopathology)
  • Retinal Neovascularization (complications, genetics, physiopathology)
  • Transgenes (genetics)
  • Vascular Endothelial Growth Factor B (genetics)

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