title: Long-term global retinal microvascular changes in a transgenic vascular endothelial growth factor mouse model.
abstract: OBJECTIVE
  Vascular endothelial growth factor (VEGF) plays a pivotal role in the pathogenesis of diabetic retinopathy. We investigated whether transgenic mice with moderate VEGF expression in photoreceptors (trVEGF029) developed changes similar to diabetic retinopathy and whether retinopathy progressed with time.
  
  
  METHODS
  Human VEGF(165) (hVEGF(165)) expression was analysed using ELISA and quantitative RT-PCR; serum glucose levels were also measured. Fundus fluorescein angiography (FA) was used to screen the degree of retinopathy from 6 weeks. Dynamic changes in the density of retinal microvasculature, as well as other changes similar to diabetic retinopathy, including retinal leucostasis, capillary endothelial cell and pericyte loss, and numbers of acellular capillaries, were quantified.
  
  
  RESULTS
  trVEGF029 mice were normoglycaemic and showed a moderate, short-term hVEGF(165) upregulation for up to 3 weeks. Changes in the retinal microvasculature not only mimicked those seen in diabetic retinopathy, but also showed similar pathological progression with time. FA at 6 weeks identified two phenotypes, mild and moderate, which were distinguished by the extent of vascular leakage. Quantitative analysis of diabetic retinopathy-like changes revealed that these parameters were tightly correlated with the initial degree of vascular leakage; low levels reflected slow and limited retinal microvascular changes in mild cases and high levels reflected more rapid and extensive changes in moderate cases.
  
  
  CONCLUSIONS
  The data suggest that even an early short-term elevation in hVEGF(165) expression might set a train of events that lead to progressive retinopathy. Induction of many features characteristic of diabetic retinopathy in trVEGF029 enables mechanisms leading to the disease state to be examined, and provides a relevant animal model for testing novel therapeutics.
authors.affiliation: Centre of Ophthalmology and Visual Science, The University of Western Australia, Nedlands, Perth, WA, Australia.
authors.forename: W-Y
authors.initials: WY
authors.lastname: Shen
authors.forename: C M
authors.initials: CM
authors.lastname: Lai
authors.forename: C E
authors.initials: CE
authors.lastname: Graham
authors.forename: N
authors.initials: N
authors.lastname: Binz
authors.forename: Y K Y
authors.initials: YK
authors.lastname: Lai
authors.forename: J
authors.initials: J
authors.lastname: Eade
authors.forename: D
authors.initials: D
authors.lastname: Guidolin
authors.forename: D
authors.initials: D
authors.lastname: Ribatti
authors.forename: S A
authors.initials: SA
authors.lastname: Dunlop
authors.forename: P E
authors.initials: PE
authors.lastname: Rakoczy
mesh_terms: D000818:Animals; D001786:Blood Glucose / Q000032:analysis; D003925:Diabetic Angiopathies / Q000378:metabolism / Q000473:pathology; D003930:Diabetic Retinopathy / Q000150:complications / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D004195:Disease Models, Animal; D018450:Disease Progression; D018921:Leukostasis / Q000150:complications / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D012171:Retinal Vessels / Q000378:metabolism / Q000473:pathology*; D013997:Time Factors; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics* / Q000378:metabolism
chemical_list: D001786:Blood Glucose; D042461:Vascular Endothelial Growth Factor A; C467480:vascular endothelial growth factor A, mouse