Expression of vascular endothelial growth factor in experimental choroidal neovascularization

Ishibashi, Tatsuro; Hata, Yoshinobu; Yoshikawa, Hiroshi; Nakagawa, Kei; Sueishi, Katsuo; Inomata, Hajime

doi:10.1007/bf00941723

Cited by 211 publications

(140 citation statements)

References 31 publications

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“…Glia-derived cells such as astrocytes present in the ganglion cell layer, Muller cells embedded in the inner nuclear layer (14,15), and macrophages recruited into the retina were described as major sources of retinal VEGF in ROP (19,20). Although retinal pigmented epithelium residing at the outer boundary of the neural retina was suggested as another source of retinal VEGF, expression of VEGF mRNA by these cells was shown to be unaffected in this model (7,15).…”

Section: Jnk1 Regulates Vegf Expression and Neovascularization In A Mmentioning

confidence: 82%

Genetic and pharmacological inhibition of JNK ameliorates hypoxia-induced retinopathy through interference with VEGF expression

Gumá

Rius

Duong-Polk

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

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Many ocular pathologies, including retinopathy of prematurity (ROP), diabetic retinopathy, and age-related macular degeneration, result in vision loss because of aberrant neoangiogenesis. A common feature of these conditions is the presence of hypoxic areas and overexpression of the proangiogenic vascular endothelial growth factor (VEGF). The prevailing current treatment, laser ablation of the retina, is destructive and only partially effective. Preventive and less destructive therapies are much more desirable. Here, we show that mice lacking c-Jun N-terminal kinase 1 (JNK1) exhibit reduced pathological angiogenesis and lower levels of retinal VEGF production in a murine model of ROP. We found that hypoxia induces JNK activation and regulates VEGF expression by enhancing the binding of phospho-c-Jun to the VEGF promoter. Intravitreal injection of a specific JNK inhibitor decreases retinal VEGF expression and reduces pathological retinal neovascularization without obvious side effects. These results strongly suggest that JNK1 plays a key role in retinal neoangiogenesis and that it represents a new pharmacological target for treatment of diseases where excessive neoangiogenesis is the underlying pathology.neoangiogenesis ͉ retinopathy of prematurity

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Section: Jnk1 Regulates Vegf Expression and Neovascularization In A Mmentioning

confidence: 82%

Genetic and pharmacological inhibition of JNK ameliorates hypoxia-induced retinopathy through interference with VEGF expression

Gumá

Rius

Duong-Polk

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

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“…The accumulation of PS-oligos at laser lesions might be associated with altered cell membranes with a higher affinity for fusion but most likely reflects the activity of the cells during the development of CNV (Zhang et al, 1993). It has been confirmed that the majority of cells that take up PS-oligo at laser lesions are proliferating RPE, macrophages, and activated choroidal cells, which are also the main sources of overexpression of VEGF in the laser-induced CNV (Ishibashi et al, 1997;Shen et al, 1998;Yi et al, 1997) and in neovascular membranes of humans (Lopez et al, 1996). This coincidentally allows us to specifically deliver DS135 into the cells overexpressing VEGF during the development of CNV.…”

Section: Shen Et Almentioning

confidence: 84%

“…VEGF is an endothelial cell-specific mitogen that plays a primary role in the angiogenic process. It is expressed before the onset of neovascularization in animal models of proliferative retinopathy and laser-induced CNV (Ishibashi et al, 1997;Shen et al, 1998;Sone et al, 1999). Overexpression of VEGF is also detected in surgically removed samples from patients with diabetic retinopathy and subfoveal CNV (Lip et al, 2000;Lopez et al, 1996).…”

mentioning

confidence: 99%

Preclinical Evaluation of a Phosphorothioate Oligonucleotide in the Retina of Rhesus Monkey

Shen

Garrett

Wang

et al. 2002

Laboratory Investigation

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SUMMARY:Overexpression of vascular endothelial growth factor (VEGF) has been strongly implicated in the development of choroidal neovascularization (CNV) in patients with age-related macular degeneration. In this study, a phosphorothioate oligonucleotide (PS-oligo) targeting both human and rat VEGF 165 genes upstream of the translation initiation code, named DS135 in this study, was evaluated for its uptake dynamics and retinal tolerance after intravitreal (IV) and subretinal (SR) injections in the rhesus monkey. Intravitreal and SR injections of a fluorescent-labeled DS135 (FL-DS135) resulted in both dose-and time-dependent uptake and persistence, and FL-DS135 remained detectable in the retina for at least 3 weeks after injection. Ophthalmic examination showed transient vitreous haze after IV delivery of a high dose but not with a low dose of FL-DS135. Histologic examination showed no evidence of retinal degeneration with respect to IV delivery. After SR delivery, however, dose-related cellular infiltration, transient residual fluid, and slight distortion of the neuroretina were observed. The biologic efficacy of DS135 was further assessed in a laser-induced CNV model, and development of CNV was determined by fluorescein angiography and histologic examination. Incomplete inhibition of CNV formation was observed after IV and SR injection of DS135, but no statistically significant difference was achieved when compared with dose-matched control of PS-oligo. Analysis of fluorescein angiogram and histologic examination showed less than 30% incidence of CNV development in this monkey model. Our study demonstrated that PS-oligos can be successfully introduced into the retina, although with potential limitations, after SR delivery. DS135, a PS-oligo targeting the VEGF gene upstream of the translation initiation code, partially inhibited CNV formation. An improved CNV model is necessary for further confirmation of the full therapeutic potency of DS135 before clinical application. (Lab Invest 2002, 82:167-182).

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“…VEGF possesses many attributes for such a role. It is strongly and preferentially induced by hypoxia in RPE cells, 14 it is invariably associated with human CNVMs and in laser CNV models in animals, 3,5,[15][16][17][18][19] it is strongly secreted from the basal side of the RPE toward the choroid, and high levels of VEGF receptors KDR and flt-4 are found on the choriocapillaris endothelium facing the RPE layer.…”

mentioning

confidence: 99%

Overexpression of Vascular Endothelial Growth Factor (VEGF) in the Retinal Pigment Epithelium Leads to the Development of Choroidal Neovascularization

Spilsbury

Garrett

Shen

et al. 2000

The American Journal of Pathology

345

214

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Vascular endothelial growth factor (VEGF) has been strongly implicated in the development of choroidal neovascularization found in age-related macular degeneration. Normally expressed in low levels, this study investigates whether the overexpression of VEGF in the retinal pigment epithelium is sufficient to cause choroidal neovascularization in the rat retina. A recombinant adenovirus vector expressing the rat VEGF 164 cDNA (AdCMV.VEGF) was constructed and injected into the subretinal space. The development of neovascularization was followed by fluorescein angiography, which indicates microvascular hyperpermeability of existing and/or newly forming blood vessels, and histology. VEGF mRNA was found to be overexpressed by retinal pigment epithelial cells and resulted in leaky blood vessels at 10 days postinjection, which was maintained for up to 31 days postinjection. By 80 days postinjection, new blood vessels had originated from the choriocapillaris, grown through the Bruch's membrane to the subretinal space, and disrupted the retinal pigment epithelium. This ultimately led to the formation of choroidal neovascular membranes and the death of overlying photoreceptor cells. By controlling the amount of virus delivered to the subretinal space, we were able to influence the severity and extent of the resulting choroidal neovascularization. These results show that even temporary overexpression of VEGF in retinal pigment epithelial cells is sufficient to induce choroidal neovascularization in the rat eye. Age-related macular degeneration is a significant cause of central vision loss in aging populations. The more severe form of age-related macular degeneration is characterized by choroidal neovascularization (CNV), in which new blood vessels grow from the choroid, through the Bruch's membrane into the subretinal space. This ultimately leads to the formation of choroidal neovascular membranes (CNVMs), from which blood and serum may leak, causing vision loss.

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Expression of vascular endothelial growth factor in experimental choroidal neovascularization

Abstract: VEGF derived from RPE cells, macrophages and Müller cells may play a role in the formation of CNV.

Cited by 211 publications

References 31 publications

Genetic and pharmacological inhibition of JNK ameliorates hypoxia-induced retinopathy through interference with VEGF expression

Genetic and pharmacological inhibition of JNK ameliorates hypoxia-induced retinopathy through interference with VEGF expression

Preclinical Evaluation of a Phosphorothioate Oligonucleotide in the Retina of Rhesus Monkey

Overexpression of Vascular Endothelial Growth Factor (VEGF) in the Retinal Pigment Epithelium Leads to the Development of Choroidal Neovascularization

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