title: Implication of the hypoxia response element of the Vegf promoter in mouse models of retinal and choroidal neovascularization, but not retinal vascular development.
abstract: Retinal neovascularization (NV) and macular edema, resulting from blood-retinal barrier (BRB) breakdown, are major causes of visual loss in ischemic retinopathies. Choroidal NV (CNV) occurs in diseases of the retinal pigmented epithelium/Bruch's membrane complex and is another extremely prevalent cause of visual loss. We used mice in which the hypoxia response element (HRE) is deleted from the vascular endothelial growth factor (vegf) promoter (Vegf(delta/delta) mice) to explore the role of induction of VEGF through the HRE in these disease processes. Compared to wild type (Vegf+/+) mice with oxygen-induced ischemic retinopathy (OIR) in which vegf mRNA levels were increased and prominent retinal NV and BRB breakdown occurred, Vegf(delta/delta) littermates with OIR failed to increase vegf mRNA levels in the retina and had significantly less retinal NV and BRB breakdown, but showed prominent dilation of some superficial retinal vessels. Vegf(+/delta) littermates with ischemic retinopathy developed comparable retinal NV to Vegf+/+ mice, exhibited intermediate levels of BRB breakdown, and did not show vasodilation. In a mouse model of CNV, due to laser-induced rupture of Bruch's membrane, the area of CNV at Bruch's membrane rupture sites was more than tenfold greater in Vegf+/+ mice than in Vegf(delta/delta) littermates. In contrast to these dramatic differences in pathologic ocular NV, Vegf(delta/delta) mice showed subtle differences in retinal vascular development compared to Vegf+/+ mice; it was slightly delayed, but otherwise normal. These data suggest that induction of VEGF through the HRE in its promoter is critical for retinal and CNV, but not for retinal vascular development.
authors.affiliation: Department of Ophthalmology, The Wilmer Eye Institute, The Johns Hopkins University School of Medicine, Baltimore, Maryland 21287-9289, USA. svinores@jhmi.edu
authors.forename: Stanley A
authors.initials: SA
authors.lastname: Vinores
authors.forename: Wei-Hong
authors.initials: WH
authors.lastname: Xiao
authors.forename: Sadia
authors.initials: S
authors.lastname: Aslam
authors.forename: Jikui
authors.initials: J
authors.lastname: Shen
authors.forename: Yuji
authors.initials: Y
authors.lastname: Oshima
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Nambu
authors.forename: Hansheng
authors.initials: H
authors.lastname: Liu
authors.forename: Peter
authors.initials: P
authors.lastname: Carmeliet
authors.forename: Peter A
authors.initials: PA
authors.lastname: Campochiaro
mesh_terms: D000818:Animals; D001813:Blood-Retinal Barrier; D020256:Choroidal Neovascularization / Q000209:etiology / Q000378:metabolism*; D003930:Diabetic Retinopathy / Q000378:metabolism; D000860:Hypoxia; D051793:Hypoxia-Inducible Factor 1 / Q000235:genetics*; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D023421:Models, Animal; D011401:Promoter Regions, Genetic; D020218:Response Elements; D012160:Retina / Q000254:growth & development* / Q000378:metabolism; D015861:Retinal Neovascularization / Q000209:etiology / Q000378:metabolism*; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics* / Q000378:metabolism
chemical_list: D051793:Hypoxia-Inducible Factor 1; D042461:Vascular Endothelial Growth Factor A