Intrachoroidal Neovascularization in Transgenic Mice Overexpressing Vascular Endothelial Growth Factor in the Retinal Pigment Epithelium

Schwesinger, Catherine; Yee, Charles; Rohan, Richard M.; Joussen, Antonia M.; Fernández, Antonio; Meyer, Tobias; Poulaki, Vassiliki; J.K., Joseph; Redmond, T. Michael; Liu, Suyan; Adamis, Anthony P.; D’Amato, Robert J.

doi:10.1016/s0002-9440(10)64063-1

Cited by 205 publications

(138 citation statements)

References 44 publications

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“…There is mounting evidence that increased VEGF expression is associated with and causes pathologic neovascularization in AMD and in animal models of AMD (Lopez et al, 1996;Frank et al, 1996;Yi et al, 1997;Baffi et al, 2000;Schwesinger et al, 2001;Grossniklaus et al, 2002;Ishida et al, 2003;Wang et al, 2003). VEGF is found in RPE in surgically excised human AMD specimens of CNV (Lopez et al, 1996;Frank et al, 1996;Grossniklaus et al, 2002).…”

Section: Vegf In Pathologic Neovascularization: Models Of Neovascularmentioning

confidence: 99%

“…VEGF has been localized to CNV in rodent models of laserinduced CNV (Bora et al, 2005;Yi et al, 1997) and genetically modified mouse models of CNV (Ambati et al, 2003). The overexpression of VEGF in RPE caused intrachoroidal neovascularization in one model (Schwesinger et al, 2001). Recombinant adeno-associated virus-mediated expression of VEGF 165 delivered through a subretinal injection caused CNV (Baffi et al, 2000;Wang et al, 2003).…”

Section: Vegf In Pathologic Neovascularization: Models Of Neovascularmentioning

confidence: 99%

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Vascular endothelial growth factor in eye disease

Penn

Madan

Caldwell

et al. 2008

Progress in Retinal and Eye Research

636

527

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Collectively, angiogenic ocular conditions represent the leading cause of irreversible vision loss in developed countries. In the U.S., for example, retinopathy of prematurity, diabetic retinopathy and age-related macular degeneration are the principal causes of blindness in the infant, working age and elderly populations, respectively. Evidence suggests that vascular endothelial growth factor (VEGF), a 40 kDa dimeric glycoprotein, promotes angiogenesis in each of these conditions, making it a highly significant therapeutic target. However, VEGF is pleiotropic, affecting a broad spectrum of endothelial, neuronal and glial behaviors, and confounding the validity of anti-VEGF strategies, particularly under chronic disease conditions. In fact, among other functions VEGF can influence cell proliferation, cell migration, proteolysis, cell survival and vessel permeability in a wide variety of biological contexts. This article will describe the roles played by VEGF in the pathogenesis of retinopathy of prematurity, diabetic retinopathy and age-related macular degeneration. The potential disadvantages of inhibiting VEGF will be discussed, as will the rationales for targeting other VEGF-related modulators of angiogenesis.

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Section: Vegf In Pathologic Neovascularization: Models Of Neovascularmentioning

confidence: 99%

Section: Vegf In Pathologic Neovascularization: Models Of Neovascularmentioning

confidence: 99%

Vascular endothelial growth factor in eye disease

Penn

Madan

Caldwell

et al. 2008

Progress in Retinal and Eye Research

636

527

View full text Add to dashboard Cite

show abstract

“…For example, growth factors such as basic FGF and VEGF-A have been injected subretinally to trigger CNV. 26 Schwesinger et al 27 overexpressed VEGF-A in the RPE, which led to intrachoroidal neovascularization. More recently, a very low-density lipoprotein receptor (VLDLR) knockout mouse was described that exhibited subretinal neovascularization, 28 but it is now believed that the neovessels are of retinal origin.…”

Section: Choroidal Neovascularizationmentioning

confidence: 99%

Spontaneous CNV in a Novel Mutant Mouse Is Associated With Early VEGF-A–Driven Angiogenesis and Late-Stage Focal Edema, Neural Cell Loss, and Dysfunction

Nagai

Leithner

Izumi-Nagai

et al. 2014

Invest. Ophthalmol. Vis. Sci.

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PURPOSE.Characterization of a mouse model of spontaneous choroidal neovascularization (sCNV) and its effect on retinal architecture and function.METHODS. The sCNV mouse phenotype was characterized by using fundus photography, fluorescein angiography, confocal scanning laser ophthalmoscopy (SLO), optical coherence tomography (OCT), ERG, immunostaining, biochemistry, and electron microscopy. A role for VEGF-A signaling in sCNV was investigated by using neutralizing antibodies and a role for macrophages explored by cell-depletion studies.RESULTS. The sCNV starts between postnatal day 10 and 15 (P10-P15), increasing in number and severity causing RPE disruption and dysfunction. Various morphological methods confirmed the choroidal origin and subretinal position of the angiogenic vessels. At approximately P25, vessels were present in the outer retina with instances of anastomosis of some sCNV lesions with the retinal vasculature. The number of CNV lesions was significantly decreased by systemic blockade of the VEGF-A pathway. Choroidal neovascularization size also was significantly modulated by reducing the number of lesion-associated macrophages. Later stages of sCNV were associated with edema, neuronal loss, and dysfunction. CONCLUSIONS.The sCNV mouse is a new model for the study of both early and late events associated with choroidal neovascularization. Pharmacological reduction in sCNV with VEGF-A antagonists and an anti-inflammatory strategy suggests the model may be useful for investigating novel targets for treating human ocular neovascular disease.Keywords: animal models, neovascularization, VEGF-A T he transformative nature of recent therapeutic developments for neovascular age-related macular degeneration (nAMD) has triggered an exponential increase in ophthalmic drug development efforts over the past decade. 1 The most prevalent assay used to benchmark potential new nAMD compounds and therapeutic strategies is rodent laser-induced choroidal neovascularization (lCNV). [2][3][4][5] This model is used to assess antiangiogenic activity and the ability to reduce vascular permeability, two hallmarks of nAMD. Moreover, because of the ease of imaging the posterior pole, lCNV is often used as a secondary pharmacology model during drug development for other conditions, such as cancer. However, the lCNV model has several limitations, including acute, intense laser injury to the photoreceptors, RPE, and choriocapillaris to induce angiogenesis, the accumulation of hypertrophic scar tissue, and a natural regression of the neovascularization. 6 Therefore, factors that initiate the CNV, and long-term analysis of the consequences of the neovessels to the retina, cannot be readily studied. Here we describe a novel genetic model of multifocal, bilateral spontaneous choroidal neovascularization (sCNV), which leads to early, persistent neovascular lesions that leak and lead to retinal edema, local gliosis and focal photoreceptor dysfunction, and death. Approximately 10% to 15% of the lesions will eventually anastomose with the...

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“…10 However, a potential drawback of these therapies is that there has been some evidence showing that suppressed expression of VEGF alone is not sufficient to inhibit CNV. [11][12][13] The initiation of a submacular wound-healing response may require a hypoxic stimulus, which in turn leads to the production of hypoxia-inducible factor-1(HIF-1), a transcription factor that functions as a master regulator of oxygen homeostasis. 14 Clinical studies have shown that the age-related changes in Bruch's membrane and the dropout of choriocapillaris cause impaired diffusion of oxygen.…”

Section: Introductionmentioning

confidence: 99%

Inhibitory efficacy of hypoxia-inducible factor 1α short hairpin RNA plasmid DNA-loaded poly (D, L-lactide-co-glycolide) nanoparticles on choroidal neovascularization in a laser-induced rat model

Zhang

et al. 2009

Gene Ther

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The aim of this study was to evaluate the possibility of poly (D, L-lactide-co-glycolide) nanoparticle (NPs) as a gene vector for functional plasmid DNA (pDNA) and to investigate its inhibitory efficacy on experimental choroidal neovascularization (CNV). We developed intravitreal administered, hypoxia-inducible factor 1a (HIF-1a) short hairpin RNA and green fluorescent protein (GFP) co-expressed pDNA-loaded NPs (pshHIF-1a NPs). CNV was induced by laser photocoagulation in 112 rats. The rats were then randomly assigned to be injected intravitreally with phosphate-buffered saline (PBS), blank NPs, naked pDNA, control pDNA NPs and pshHIF-1a NPs, respectively, and non-injection group was set as the control. Immunofluorescence staining, fluorescein fundus angiography and histologic analysis were performed to evaluate the inhibitory efficacy on CNV. The results showed that the expression of GFP preferentially localized in the retinal pigment epithelium cell layer and lasted for 4 weeks. The fluorescein leakage areas of CNV were significantly larger in the PBS, blank NPs, control pDNA NPs, non-injection group and naked pDNA group than in pshHIF-1a NPs group (Po0.01). The mean thickness of the CNV lesions in the intravitreally pshHIF1a NPs-treated group was significantly smaller than other groups (Po0.01). No signs of functional or ultrastructural destruction in retina were detected. Therefore, pshHIF-1a NPs may act as a novel therapeutic option to transfer specific pDNA and inhibit the formation of experimental CNV.

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Intrachoroidal Neovascularization in Transgenic Mice Overexpressing Vascular Endothelial Growth Factor in the Retinal Pigment Epithelium

Cited by 205 publications

References 44 publications

Vascular endothelial growth factor in eye disease

Vascular endothelial growth factor in eye disease

Spontaneous CNV in a Novel Mutant Mouse Is Associated With Early VEGF-A–Driven Angiogenesis and Late-Stage Focal Edema, Neural Cell Loss, and Dysfunction

Inhibitory efficacy of hypoxia-inducible factor 1α short hairpin RNA plasmid DNA-loaded poly (D, L-lactide-co-glycolide) nanoparticles on choroidal neovascularization in a laser-induced rat model

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