Upregulation of vascular endothelial growth factor (VEGF) in the retinas of transgenic mice overexpressing interleukin-1ß (IL-1ß) in the lens and mice undergoing retinal degeneration

S.A. Vinores1, W.-H. Xiao1, R. Zimmerman1, S.M. Whitcup2,3 and E.F. Wawrousek2

1The Wilmer Eye Institute, Johns Hopkins University School of Medicine, Baltimore,
2National Eye Institute, National Institutes of Health, Bethesda and 32525 Dupont Dr., Allergan, Irvine, CA, USA

Offprint requests to: S.A. Vinores, 825 Maumenee Bldg, The Wilmer Eye Institute, Johns Hopkins University, School of Medicine, Baltimore, MD 21287-9289, USA. Fax: 410-502-5382. e-mail: svinores@jhmi.edu

 

Summary. IL-1ß is a pro-inflammatory agent associated with angiogenesis and increased vascular permeability. To determine whether IL-1ß elicits these responses through an upregulation of VEGF, transgenic mice that overexpress IL-1ß in the lens were evaluated at various time points for the localization of VEGF, the location and extent of blood-retinal barrier (BRB) breakdown, and the origin and extent of neovascularization (NV). In homozygous and heterozygous transgenic mice, but not controls, intense VEGF immunoreactivity was scattered throughout the retina at postnatal days 5-7 (P5-7), just after the onset of inflammatory cell infiltration. VEGF staining in the retina remained widespread, but weak from P9-15. Beginning at P15, the intensity of VEGF immunoreactivity achieved a second peak, which it maintained through adulthood. This peak coincided with significant retinal destruction due to massive inflammation. The onset of BRB breakdown coincided with the upregulation of VEGF (P5-7) and widespread BRB breakdown was demonstrated from about P9. From P9-12, aggregates of cells positive for Griffonia simplicifolia isolectin-B4, a marker for vascular endothelial cells, formed on the retinal surface. These cells migrated into the retina at P12-15 with the more superficial cells forming a network of vessels and the deeper cells remaining in small clusters, thus demonstrating that NV occurs much later than BRB breakdown. Non-transgenic FVB/N mice, which undergo retinal degeneration beginning at about P9, also demonstrate the latter peak of VEGF upregulation and the accompanying BRB breakdown, but not the early upregulation. VEGF immunostaining of transgenic and non-transgenic mouse retinas was eliminated by pre-incubation of the VEGF antibodies with VEGF peptide. The data suggest that the early peak of VEGF upregulation (P5-7) and its accompanying BRB breakdown is due to IL-1ß expression and is likely to be dependent on inflammatory cell infiltration. The latter peak appears to be related to retinal destruction. Histol. Histopathol. 18, 797-810 (2003)

Key words: Interleukin-1ß, Vascular endothelial growth factor, Blood-retinal barrier, Retinal degeneration, Angiogenesis

DOI: 10.14670/HH-18.797