In Vivo Monitoring of VEGF-Induced Retinal Damage in the Kimba Mouse Model of Retinal Neovascularization

Purpose: To monitor retinal and vascular changes associated with neovascularization, which were generated through photoreceptor-specific overexpression of human vascular endothelial growth factor (hVEGF), in transgenic trVEGF029 (Kimba) mice. Materials and Methods: The Spectralis Heidelberg Retina Angiography and Optical Coherence Tomography (HRA+OCT) imaging device was used to track changes in the retina and retinal vasculature of Kimba mouse eyes (n = 32) and control C57Bl/6J mouse eyes (n = 20) at 4, 8, 12, 16, and 20 weeks of age. Results: Retinal vascular leakage, focal dilated vessel, vessel tortuosity, attenuated vessel, venous beading, capillary dropout, retinal non-perfusion, neovascularization, and focal retinal detachment were observed in Kimba mouse eyes. Through track changes, we detected edema in the peripheral part of the retina of 2/32 Kimba mouse eyes examined. The retinae of the Kimba mice were significantly thinner than control mice retinae at all ages of the mice assessed (p < 0.01). Conclusions: In vivo monitoring of retinal vascular and neural retinal changes in the Kimba mice using the Spectralis HRA+OCT imaging device allowed us to assess and track VEGF-induced damages in great detail and in real-time. Real-time monitoring of these changes can be used to study the interplay between VEGF overexpression and other molecular factors and to monitor dynamic retinal changes following therapeutic intervention.

[1]  E. Rakoczy,et al.  rAAV.sFlt-1 gene therapy achieves lasting reversal of retinal neovascularization in the absence of a strong immune response to the viral vector. , 2009, Investigative Ophthalmology and Visual Science.

[2]  Marinko V Sarunic,et al.  In vivo imaging of the mouse model of X-linked juvenile retinoschisis with fourier domain optical coherence tomography. , 2009, Investigative ophthalmology & visual science.

[3]  A. Brucker AGE-RELATED MACULAR DEGENERATION , 2009, Retina.

[4]  Andreas Wenzel,et al.  Spectral domain optical coherence tomography in mouse models of retinal degeneration. , 2009, Investigative ophthalmology & visual science.

[5]  J. Kerrison,et al.  Diabetic retinopathy and angiogenesis. , 2009, Current diabetes reviews.

[6]  Magali Saint-Geniez,et al.  Endogenous VEGF Is Required for Visual Function: Evidence for a Survival Role on Müller Cells and Photoreceptors , 2008, PloS one.

[7]  Salvatore Grisanti,et al.  The role of vascular endothelial growth factor and other endogenous interplayers in age-related macular degeneration , 2008, Progress in Retinal and Eye Research.

[8]  E. Rakoczy,et al.  VEGF-induced choroidal damage in a murine model of retinal neovascularisation , 2008, British Journal of Ophthalmology.

[9]  E. Rakoczy,et al.  Early vascular and neuronal changes in a VEGF transgenic mouse model of retinal neovascularization. , 2006, Investigative ophthalmology & visual science.

[10]  D. Guidolin,et al.  Long-term global retinal microvascular changes in a transgenic vascular endothelial growth factor mouse model , 2006, Diabetologia.

[11]  E. Chew,et al.  Macular telangiectasia: a simplified classification. , 2006 .

[12]  I. Constable,et al.  Long-term evaluation of AAV-mediated sFlt-1 gene therapy for ocular neovascularization in mice and monkeys. , 2005, Molecular therapy : the journal of the American Society of Gene Therapy.

[13]  W. Shen,et al.  Generation of transgenic mice with mild and severe retinal neovascularisation , 2005, British Journal of Ophthalmology.

[14]  M. Bartoli,et al.  Vascular endothelial growth factor and diabetic retinopathy: pathophysiological mechanisms and treatment perspectives , 2003, Diabetes/metabolism research and reviews.

[15]  Matthew D. Davis,et al.  Proposed international clinical diabetic retinopathy and diabetic macular edema disease severity scales. , 2003, Ophthalmology.

[16]  S. Hayreh Management of Central Retinal Vein Occlusion , 2003, Ophthalmologica.

[17]  P. Rakoczy,et al.  Potential long-term inhibition of ocular neovascularisation by recombinant adeno-associated virus-mediated secretion gene therapy , 2002, Gene Therapy.

[18]  J. Tarbell,et al.  Vascular permeability in experimental diabetes is associated with reduced endothelial occludin content: vascular endothelial growth factor decreases occludin in retinal endothelial cells. Penn State Retina Research Group. , 1998, Diabetes.

[19]  R. Folberg,et al.  Vascular endothelial growth factor upregulation in human central retinal vein occlusion. , 1998, Ophthalmology.

[20]  L. Aiello,et al.  Hypoxic regulation of vascular endothelial growth factor in retinal cells. , 1995, Archives of ophthalmology.

[21]  J. Stone,et al.  Development of retinal vasculature is mediated by hypoxia-induced vascular endothelial growth factor (VEGF) expression by neuroglia , 1995, The Journal of neuroscience : the official journal of the Society for Neuroscience.

[22]  Lois E. H. Smith,et al.  Vascular endothelial growth factor/vascular permeability factor expression in a mouse model of retinal neovascularization. , 1995, Proceedings of the National Academy of Sciences of the United States of America.

[23]  L. Aiello,et al.  Vascular endothelial growth factor in ocular fluid of patients with diabetic retinopathy and other retinal disorders. , 1994, The New England journal of medicine.

[24]  J. Folkman,et al.  Synthesis and secretion of vascular permeability factor/vascular endothelial growth factor by human retinal pigment epithelial cells. , 1993, Biochemical and biophysical research communications.

[25]  E. Keshet,et al.  Vascular endothelial growth factor induced by hypoxia may mediate hypoxia-initiated angiogenesis , 1992, Nature.

[26]  D L DeMets,et al.  The Wisconsin Epidemiologic Study of Diabetic Retinopathy. VI. Retinal photocoagulation. , 1987, Ophthalmology.

[27]  H. Dvorak,et al.  A highly conserved vascular permeability factor secreted by a variety of human and rodent tumor cell lines. , 1986, Cancer research.

[28]  A. Patz,et al.  Studies on retinal neovascularization. Friedenwald Lecture. , 1980, Investigative ophthalmology & visual science.

[29]  R. Wright Vascular Permeability in Experimental Brain Tumors , 1967, Angiology.

[30]  G. Hageman,et al.  Age-Related Macular Degeneration (AMD) , 2008 .

[31]  G. Lang,et al.  [Retinal angiomatous proliferation in age-related macular degeneration]. , 2006, Klinische Monatsblatter fur Augenheilkunde.

[32]  T. Sano,et al.  [Diabetic retinopathy]. , 2001, Nihon rinsho. Japanese journal of clinical medicine.

[33]  R. Klein,et al.  The Wisconsin Epidemiologic Study of Diabetic Retinopathy. XV. The long-term incidence of macular edema. , 1995, Ophthalmology.