Different effects of various anti‐angiogenic treatments in an experimental mouse model of retinopathy of prematurity

Heiduschka, Peter; Plagemann, Tanja; Li, Lü; Alex, Anne F.; Eter, Nicole

doi:10.1111/ceo.13368

Cited by 8 publications

(4 citation statements)

References 33 publications

(50 reference statements)

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“…The selective visualization of neovascular vessels in the physiologically avascular outer retinal layer initially, followed by substantial decrease of laser lesion size and vessel morphology as compared to the control group over time is in accordance with the current knowledge of CNV development and treatment effects of anti-VEGF agents, as previously shown in the rodent model of laser-induced CNV and in patients with CNV in the presence of various degenerative retinal-choroidal diseases, including AMD. 20,21,[38][39][40][41] Furthermore, the direct correlation of in vivo findings by ex vivo analysis in the same animal further confirms these observations, also revealing consistent results with regard to quantification of individual lesion size.…”

Section: Discussionsupporting

confidence: 78%

Imaging of Therapeutic Effects of Anti-Vascular Endothelial Growth Factor Inhibitors by Optical Coherence Tomography Angiography in a Rat Model

Meyer

Marx

Strack

et al. 2020

Trans. Vis. Sci. Tech.

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The aim of the study was to investigate optical coherence tomography angiography (OCTA) as a high-resolution in vivo imaging modality for monitoring therapeutic response to different vascular endothelial growth factor inhibitors in the rat model of laser-induced choroidal neovascularization (CNV). Further, OCTA findings were compared with fluorescein angiography (FA) and fluorescence microscopy. Methods: Laser treatment at day (D)0 was followed by intravitreal injection of aflibercept, AF564, and NaCl in dark agouti rats. Imaging with OCTA and FA was performed at D2, D7, D14, and D21. OCTA was compared to FA as well as confocal imaged flat mounts and analysis included quantification of CNV area, pixel intensity, vessel density, and number of vessel junctions. Results: Within laser lesions, neovascularization were visible especially in deeper retinal layers on OCTA, but not on FA images. Using OCTA, mean CNV area (D21) at the level of the outer nuclear layer (ONL) was 0.017 mm 2 following aflibercept administration, 0.016 mm 2 following AF564 and 0.026 mm 2 following NaCl injection (P = 0.04 and P = 0.03). Similar differences between treatment groups were determined by FA and histology, although the overall CNV area was always larger on FA due to dye leakage (P ≤ 0.0001, all layers). Conclusions: Compared to FA, OCTA imaging allows for a more precise and quantitative analysis of new blood vessel formation and therapeutic response to vascular endothelial growth factor (VEGF)-inhibitors, whereas it does not permit assessment of leakage. Translational Relevance: These findings suggest that OCTA may be particularly useful for the investigation of new treatment targets in the animal model.

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Section: Discussionsupporting

confidence: 78%

Imaging of Therapeutic Effects of Anti-Vascular Endothelial Growth Factor Inhibitors by Optical Coherence Tomography Angiography in a Rat Model

Meyer

Marx

Strack

et al. 2020

Trans. Vis. Sci. Tech.

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“…Bevacizumab, a VEGF protein-neutralizing antibody, is known to effectively inhibit angiogenesis in various cancers and DR [37][38][39]. In addition, tyrosine kinase inhibitors such as sunitinib and sorafenib inhibit angiogenesis by suppressing VEGF receptor tyrosine kinases and are also known to be effective against various cancers and ocular diseases [40][41][42][43][44][45]. However, these drugs are expensive or cause serious toxicities [46].…”

Section: Discussionmentioning

confidence: 99%

A 60% Edible Ethanolic Extract of Ulmus davidiana Inhibits Vascular Endothelial Growth Factor-Induced Angiogenesis

et al. 2021

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As abnormal angiogenesis is associated with exacerbation of various diseases, precise control over angiogenesis is imperative. Vascular endothelial growth factor (VEGF), the most well-known angiogenic factor, binds to VEGF receptor (VEGFR), activates various signaling pathways, and mediates angiogenesis. Therefore, blocking the VEGF-induced angiogenic response-related signaling pathways may alleviate various disease symptoms through inhibition of angiogenesis. Ulmus davidiana is a safe natural product that has been traditionally consumed, but its effects on endothelial cells (ECs) and the underlying mechanism of action are unclear. In the present study, we focused on the effect of a 60% edible ethanolic extract of U. davidiana (U60E) on angiogenesis. U60E inhibited the VEGF-mediated proliferation, tube formation, and migration ability of ECs. Mechanistically, U60E inhibited endothelial nitric oxide synthase activation and nitric oxide production by blocking the protein kinase B signaling pathway activated by VEGF and consequently inhibiting proliferation, tube formation, and migration of ECs. These results suggest that U60E could be a potential and safe therapeutic agent capable of suppressing proangiogenic diseases by inhibiting VEGF-induced angiogenesis.

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“…There are a limited number of animal studies in the literature that have evaluated the effects of aflibercept on retinal vasculature exposed to a hyperoxic state. These studies noted that although aflibercept promoted neovascular tuft regression, higher doses inhibited normal retinal revascularization and potentially led to permanent changes in neuroretinal structures [23-25]. It has been postulated that this is secondary to differences in binding of vitreous VEGF and retinal VEGF, which is a factor in normal retinal angiogenesis.…”

Section: Discussionmentioning

confidence: 99%

“…Regressed neovascularization with an increase in avascular retina was also found in a mouse OIR model, along with corresponding decrease in electroretinographic amplitudes [24]. Mouse OIR models evaluating the effect of PlGF modulation (sunitinib) and/or VEGF blockade (aflibercept) found inhibition of neovascularization in both groups, with the PlGF-inhibited eyes showing impaired physiologic angiogenesis [25].…”

Section: Introductionmentioning

confidence: 99%

Efficacy of Aflibercept Treatment and Its Effect on the Retinal Perfusion in the Oxygen-Induced Retinopathy Mouse Model of Retinopathy of Prematurity

et al. 2020

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Introduction: Bevacizumab and ranibizumab, which are anti-vascular endothelial growth factor (VEGF) medications, are used frequently in the treatment for retinopathy of prematurity (ROP) in infants. Aflibercept, or VEGF Trap, has been used anecdotally, but translation and clinical studies are lacking. Objective: This study investigates the efficacy of aflibercept at reducing areas of non-perfused retina and studies its effect on normal angiogenesis in the oxygen-induced retinopathy mouse model of ROP. Methods: C57BL/6 J mice were assigned to room air control (n = 21 eyes) or hyperoxia with 75% oxygen (n = 84 eyes). The hyperoxic mice were assigned to 1 of 3 groups: 0 ng (n = 14 eyes), 100 ng (n = 35 eyes), or 1,000 ng (n = 35 eyes) of intravitreal aflibercept administered on postnatal day 14. Eyes were enucleated at PN17 and PN25 postinjection. Retinas were stained with anti-collagen IV antibody and photographed with microscopy. Areas of perfused and non-perfused retina were quantified using ImageJ software. Statistical comparisons were made using ANOVA with Tukey post hoc comparisons. Results: At PN17, there was no significant difference in the area of non-perfused retina between the hyperoxic control and the 100 and 1,000 ng aflibercept groups. At PN25, the 100 ng (p < 0.05) and 1,000 ng (p = 0.008) treatment groups displayed less non-perfusion compared to hyperoxic controls. At the 1,000 ng dose, there was increased non-perfusion compared to the 100 ng dose (p = 0.02). There was reduced non-perfusion by PN25 compared to PN17 for the 100 ng group (p < 0.05), with no difference in the 1,000 ng group. Conclusions: The study shows that the area of non-perfused retina decreases effectively with aflibercept at PN25 with 100 ng dosage. With the 1,000 ng dosage, there is an inhibition of the physiologic angiogenesis with a higher area of non-perfused retina.

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Different effects of various anti‐angiogenic treatments in an experimental mouse model of retinopathy of prematurity

Cited by 8 publications

References 33 publications

Imaging of Therapeutic Effects of Anti-Vascular Endothelial Growth Factor Inhibitors by Optical Coherence Tomography Angiography in a Rat Model

Imaging of Therapeutic Effects of Anti-Vascular Endothelial Growth Factor Inhibitors by Optical Coherence Tomography Angiography in a Rat Model

A 60% Edible Ethanolic Extract of Ulmus davidiana Inhibits Vascular Endothelial Growth Factor-Induced Angiogenesis

Efficacy of Aflibercept Treatment and Its Effect on the Retinal Perfusion in the Oxygen-Induced Retinopathy Mouse Model of Retinopathy of Prematurity

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