Expression and Role of VEGF in the Adult Retinal Pigment Epithelium

Ford, Knatokie Marie; Saint‐Geniez, Magali; Walshe, Tony E.; Zahr, Alisar S.; D'Amore, Patricia A.

doi:10.1167/iovs.11-8353

Cited by 156 publications

(132 citation statements)

References 39 publications

(53 reference statements)

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“…Failure in RPE differentiation results in attenuation of VEGF expression, which is the likely molecular mechanism for atrophy of the choriocapillaris. RPE cells express high amounts of VEGF during embryonic development and in adult life (Ford et al 2011), which are essential for both the formation and the maintenance of the choriocapillaris. Conditional VEGF deficiency in the developing RPE results in the absence of the choriocapillaris in mutant mice (Marneros et al 2005;Le et al 2010), and conditional deletion of VEGF in the adult mouse RPE rapidly leads to ablation of the choriocapillaris .…”

Section: Discussionmentioning

confidence: 99%

Epithelial–mesenchymal transition of the retinal pigment epithelium causes choriocapillaris atrophy

Ohlmann

Scholz

Koch

et al. 2016

Histochem Cell Biol

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Epithelial-to-mesenchymal transition (EMT) of the retinal pigment epithelium (RPE) is commonly observed at sites of choroidal neovascularization in patients suffering from age-related macular degeneration. To learn in an experimental model how RPE EMT affects the biology of the choroidal vasculature, we studied transgenic mice (βB1-TGF-β1) with ocular overexpression of transforming growth factor-β1 (TGF-β1). RPE EMT was detectable at postnatal day (P)1 and included marked structural and functional alterations such as loss of the outer blood-retina barrier and reduced mRNA expression of the RPE-characteristic molecules Rlbp1, Rpe65, Rbp1 and Vegfa. Moreover, vascular endothelial growth factor (VEGF) was not detectable by immunohistochemistry at the RPE/choroid interface, while RPE cells stained intensely for α-smooth muscle actin. The choriocapillaris, the characteristic choroidal capillary network adjacent to the RPE, developed normally and was not obviously changed in embryonic transgenic eyes but was absent at P1 indicating its atrophy. At around the same time, photoreceptors stopped to differentiate and photoreceptor apoptosis was abundant in the second week of life. Structural changes were also seen in the retinal vasculature of transgenic animals, which did not form intraretinal vessels, and the hyaloid vasculature, which did not regress. In addition, the amounts of retinal HIF-1α and its mRNA were markedly reduced. We conclude that high amounts of active TGF-β1 in the mouse eye cause transdifferentiation of the RPE to a mesenchymal phenotype. The loss of epithelial differentiation leads to the diminished synthesis of RPE-characteristic molecules including that of VEGF. Lack of RPE-derived VEGF causes atrophy of the choriocapillaris, a scenario that disrupts photoreceptor differentiation and finally results in photoreceptor apoptosis. Lack of retinal vessel formation and of hyaloid vessel regression might be caused by the decrease in the metabolic requirements of the neuroretina leading to low amounts of retinal HIF-1α. In summary, our data indicate that failure of RPE differentiation may well precede and cause atrophy of the choriocapillaris. In contrast, RPE EMT is not sufficient to cause choroidal neovascularization.

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Section: Discussionmentioning

confidence: 99%

Epithelial–mesenchymal transition of the retinal pigment epithelium causes choriocapillaris atrophy

Ohlmann

Scholz

Koch

et al. 2016

Histochem Cell Biol

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“…These results suggest that low levels of ROS VEGF and VEGF 165 b proteins. Although expression of VEGF proteins has been previously described in several in vitro retinal cells [29,30] the co-localization of VEGF and VEGF 165 b in D407 RPE cells was unknown. Previous studies have also shown that in culture RPE cells, VEGF 165 is one of the predominant isoforms expressed, from all the members of the VEGF family [29,30].…”

Section: Glucose Induce Ros Production In Rpe Cellsmentioning

confidence: 99%

“…Although expression of VEGF proteins has been previously described in several in vitro retinal cells [29,30] the co-localization of VEGF and VEGF 165 b in D407 RPE cells was unknown. Previous studies have also shown that in culture RPE cells, VEGF 165 is one of the predominant isoforms expressed, from all the members of the VEGF family [29,30]. RPE cells were exposed to different glucose concentrations to mimic a physiological (5.5 mM) and a diabetic (25 mM) condition and it was found that VEGF and VEGF 165 b were differently regulated by glucose.…”

Section: Glucose Induce Ros Production In Rpe Cellsmentioning

confidence: 99%

Oxidative stress modulates the expression of VEGF isoforms in the diabetic retina

Simão¹,

Bitoque²,

Silva³

2016

New Front Ophthalmol

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Change in levels of vascular endothelial growth factors (VEGF) isoforms is a feature of diabetic retinopathy. To better characterize the expression of VEGFa and VEGF 165 b isoforms in the diabetic retina and to explore how oxidative stress influences the balance between these molecules, we have used the Ins2 Akita mouse model of diabetes. Retinal tissue collected from wild-type and Ins2Akita mice, together with D407 retinal pigment epithelial (RPE) cells were used as experimental models. The retina of the Ins2Akita diabetic mice was shown to have decreased levels of the anti-angiogenic VEGF 165 b protein and a high production of reactive oxygen species (ROS). High glucose deregulated the expression of VEGF proteins as well as the production of ROS in RPE cells. Physiological levels of H 2 O 2 were found to preserve the equilibrium between VEGF isoforms in RPE cells while pathological levels down-regulated the VEGF 165 b. Besides hyperglycemia, oxidative stress also contributes to disrupt the equilibrium between pro-and anti-angiogenic factors in the retina, a profile frequently found in retinal pathologies.Abbreviations: AMD -age-related macular degeneration; BRB -blood-retinal barrier; DR -diabetic retinopathy; PEDF -pigment epithelium-derived; factor RPE -retinal pigment epithelial; ROSreactive oxygen species; VEGF -vascular endothelial growth factor

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“…16 Moreover, the neutralization of VEGF in cultured RPE led to increased cell death, and VEGF neutralization in vivo resulted in damage to the RPE-choroid complex, including vacuolization, loss of association with photoreceptor outer segments, and decreased choriocapillaris fenestrations. 17 We acknowledge that the present study has a number of limitations, including the reduced number of patients, the short-term follow-up, and the subjective classification of the FAF patterns of the CNV. An additional shortcoming is the absence of a control group providing a more precise appraisal of the anti-VEGF effects.…”

Section: Discussionmentioning

confidence: 91%

Fundus Autofluorescence Changes After Ranibizumab Treatment for Subfoveal Choroidal Neovascularization Secondary to Pathologic Myopia

Parodi¹,

Iacono

Sacconi³

et al. 2015

American Journal of Ophthalmology

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Expression and Role of VEGF in the Adult Retinal Pigment Epithelium

Abstract: These results indicate that VEGF plays a critical role in survival and maintenance of RPE integrity. Potential undesired off-target effects should be considered with chronic use of anti-VEGF agents.

Cited by 156 publications

References 39 publications

Epithelial–mesenchymal transition of the retinal pigment epithelium causes choriocapillaris atrophy

Epithelial–mesenchymal transition of the retinal pigment epithelium causes choriocapillaris atrophy

Oxidative stress modulates the expression of VEGF isoforms in the diabetic retina

Fundus Autofluorescence Changes After Ranibizumab Treatment for Subfoveal Choroidal Neovascularization Secondary to Pathologic Myopia

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