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S.F. Hackett, T.W. Lauer, C.J. Weitz, P.A. Campochiaro; Expression of a Constitutively Active Form of HIF–1 in Photoreceptors Causes Retinal and Subretinal Neovascularization . Invest. Ophthalmol. Vis. Sci. 2005;46(13):4192.
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Purpose: Hypoxia has been implicated in the development of retinal neovascularization (NV) and diabetic macular edema, and has been hypothesized to play a role in the development of choroidal NV (CNV) due to age–related macular degeneration. Hypoxia–inducible factor 1 (HIF–1), a transcription factor stabilized by hypoxia, is a key regulator of hypoxia–mediated gene expression. In this study, we sought to explore the effects of increased levels of HIF–1 in the retina. Methods: Double transgenic mice with doxycycline–inducible expression of HIF–1α in photoreceptors were generated that when treated with doxycycline, express constitutively active HIF–1α which binds with HIF–1ß to produce active HIF–1. Adult double hemizygous transgenic mice were treated with 2 mg/ml doxycycline in their drinking water and euthanized after 2 or 6 weeks. The retina was removed from one eye and total RNA was isolated for real time PCR. The other eye was fixed and either frozen for cryosections or embedded in plastic for thin sections. Cryosections were stained with Griffonia simplicifolia lectin to visualize the retinal and choroidal vasculature. Results: Compared to untreated double transgenics, those treated with doxycycline for 2 or 6 weeks showed increased levels of mRNA for vascular endothelial growth factor, angiopoietin 2, and placental growth factor. Retinas appeared morphologically normal after 2 weeks of doxycycline treatment, but after 6 weeks of treatment there were several vascular abnormalities including dilation of retinal vessels, NV on the surface of the retina, NV sprouts from the deep capillaries extending into the outer nuclear layer, and CNV. Conclusions: Overexpression of a constitutively active form of HIF–1α in photoreceptors causes increased expression of proangiogenic factors and is sufficient to cause NV arising from the superficial vessels, the deep capillary bed, and the choriocapillaris.
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