Vascular Endothelial Growth Factor as an Autocrine Survival Factor for Retinal Pigment Epithelial Cells under Oxidative Stress via the VEGF-R2/PI3K/Akt

Byeon, Suk Ho; Lee, Sung Chul; Choi, Soo Hyun; Lee, Hyung Keun; Lee, Joon‐Hyung; Chu, Young Kwang; Kwon, Oh Woong

doi:10.1167/iovs.09-4144

Cited by 111 publications

(95 citation statements)

References 41 publications

(52 reference statements)

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“…As the tissue deteriorates during cultivation, the induction of VEGF-A is most likely a survival factor which is induced as the organ culture ages [26]. VEGF-A has recently been shown to be an autocrine survival factor for RPE cells [27], where the inhibition of VEGF or VEGF-R2 signaling results in a higher susceptibility towards oxidative stress. Furthermore, VEGF is an important factor for the vascularization of the choroid [28] and has protective effects on neurons [29].…”

Section: Discussionmentioning

confidence: 99%

Nicotine reduces VEGF-secretion and phagocytotic activity in porcine RPE

Klettner

Doths

Roider

2011

Graefes Arch Clin Exp Ophthalmol

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Section: Discussionmentioning

confidence: 99%

Nicotine reduces VEGF-secretion and phagocytotic activity in porcine RPE

Klettner

Doths

Roider

2011

Graefes Arch Clin Exp Ophthalmol

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“…Extracellular VEGF-A in the supernatant was blocked by bevacizumab, so that a significant increase in total VEGF-A was not measurable by our methods. Yet, a significantly higher extracellular concentration of VEGF-A close-by the cells could be expected, which may activate autocrine survival pathways via VEGFR-2/PI3K-Akt [28,35]. Another explanation could be an intracrine survival loop mechanism of VEGF-A and its receptors to promote cell survival as shown for other cell types [36][37][38].…”

Section: Discussionmentioning

confidence: 99%

“…In various cells, VEGF-A expression is triggered through oxidative stress and functions as an autocrine survival factor [27,28]. Several mechanisms have been elaborated to explain the protective effect mediated by VEGF-A against oxidative stress [29,30].…”

Section: Discussionmentioning

confidence: 99%

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Fc Receptor Inhibition Reduces Susceptibility to Oxidative Stress in Human RPE Cells Treated with Bevacizumab, but not Aflibercept

Ranjbar

Brinkmann

Zapf

et al. 2016

Cell Physiol Biochem

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Background/Aims: VEGF-A is induced by oxidative stress, and functions as a survival factor for various cell types, including retinal pigment epithelial (RPE) cells. Anti-vascular endothelial growth factor (VEGF) drugs like aflibercept and bevacizumab have shown to be most effective in treating neovascular age-related macular degeneration (AMD), however uptake of the drugs might lead to interference with cell physiology. Herein, we evaluated the significance of the Fc receptor (FcR) within this context and moreover explored the impact of VEGF inhibition under normal conditions as well as under oxidative stress, in terms of potential adverse effects. Methods: ARPE-19 (human RPE) cells were treated with aflibercept and bevacizumab in presence or absence of H₂O₂ as oxidative stress stimulus. After 24h cells were evaluated for drug uptake, VEGF-A expression and secretion, levels of intracellular reactive oxygen species (ROS) as well as cell proliferation. Experiments were repeated with cells being pre-incubated with an FcR inhibitor prior to drug application. Results: Both drugs inhibited extracellular levels of VEGF-A and were taken up into the RPE, resulting in significantly reduced intracellular levels of VEGF-A. When oxidative stress was applied, intracellular ROS levels in cells treated with both drugs rose, and cell proliferation was reduced. Prior incubation with the FcR inhibitor lessened the uptake of bevacizumab, but not aflibercept into RPE cells, and simultaneously enhanced cell survival under oxidative stress conditions. Conclusions: Our results indicate that uptake and accumulation of aflibercept and bevacizumab within RPE cells affect the intracellular VEGF-A metabolism negatively, leading to a biologically relevant reduced cell survival under oxidative stress. The FcR plays a substantial role in the uptake of bevacizumab, but not aflibercept, which allows an enhanced RPE cell survival through FcR blockage in an environment dominated by oxidative stress, as clinically significant for various inflammatory retinal disorders.

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“…Ford et al 22 concluded that VEGF plays a critical role in survival and maintenance of RPE integrity, evidenced by transient RPE degenerative changes after systemic VEGF neutralization in the murine retina. VEGF is strongly induced by oxidative stress in the RPE cells 23 and during relative retinal ischemia. 24 Although there is no documented evidence of VEGF implicating SRF development post-SLT, we pose the question that RPE cells in distress, as evidenced by the pigmentary changes and epithelial defect noted in our patient and as supported in the literature, may have released VEGF, which potentially contributed to the development of SRF and serous foveal detachment as demonstrated on OCT and FFA imaging.…”

Section: Discussionmentioning

confidence: 99%

Bilateral Subretinal Fluid Mimicking Subretinal Neovascularization Within 24 Hours After Selective Laser Trabeculoplasty

Phillis

Bourke

2016

Journal of Glaucoma

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The sudden onset of loss of vision and the development of subfoveal SRF within 24 hours of SLT strongly suggests cause and effect. This previously unreported clinical entity of bilateral SRF within 24 hours of SLT may be secondary to an intraocular inflammatory cascade, similar to previous hypotheses regarding 3 cases of cystoid macular edema post-SLT. Given the dramatic initial loss of vision and compromised long-term visual outcome, clinicians and patients need to be informed of this new clinical entity of SLT associated with SRF and permanent retinal pigment epithelial changes.

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Vascular Endothelial Growth Factor as an Autocrine Survival Factor for Retinal Pigment Epithelial Cells under Oxidative Stress via the VEGF-R2/PI3K/Akt

Abstract: Autocrine VEGF-A enhanced RPE cell survival under oxidative stress; the autocrine VEGF-A/VEGF-R2/PI3K/Akt pathway is involved. Neutralization of VEGF-A signaling, as in eyes with age-related macular degeneration, may influence RPE cell survival.

Cited by 111 publications

References 41 publications

Nicotine reduces VEGF-secretion and phagocytotic activity in porcine RPE

Nicotine reduces VEGF-secretion and phagocytotic activity in porcine RPE

Fc Receptor Inhibition Reduces Susceptibility to Oxidative Stress in Human RPE Cells Treated with Bevacizumab, but not Aflibercept

Bilateral Subretinal Fluid Mimicking Subretinal Neovascularization Within 24 Hours After Selective Laser Trabeculoplasty

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