&lt;em&gt;In Vivo&lt;/em&gt; Vascular Injury Readouts in Mouse Retina to Promote Reproducibility

Chen, Claire W.; Potenski, Anna M.; Ortiz, Crystal K. Colón; Avrutsky, Maria I.; Troy, Carol M.

doi:10.3791/63782

Cited by 3 publications

(8 citation statements)

References 27 publications

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“…Retinal injury following RVO is significantly associated with microvascular ischemia. To evaluate the evolution of capillary nonperfusion, we analyzed retinal OCTs for DRIL (disorganization of retinal inner layers) ( Avrutsky et al, 2020 ; Chen et al, 2022 ). DRIL measurements revealed inner retinal nonperfusion across approximately 51% of OCT B-scan length in vehicle treated animals, with no significant temporal trends across the duration of the study ( Figures 2 , 3A ).…”

Section: Resultsmentioning

confidence: 99%

“…Detailed OCT imaging and analysis protocols for the RVO model are described in ( Chen et al, 2022 ).…”

Section: Methodsmentioning

confidence: 99%

“…In this model, an image-guided laser system is used to create a localized occlusion to one or more branch retinal veins. Optimized RVO induction and evaluation protocols enable highly reproducible measurement of retinal edema, inflammation, and neuronal injury ( Colón Ortiz et al, 2021 ; Chen et al, 2022 ). Consistent with clinical findings, inhibiting VEGF signaling attenuates retinal edema and improves retinal nonperfusion following experimental RVO ( Fuma et al, 2017 ).…”

Section: Introductionmentioning

confidence: 99%

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Caspase-9 inhibition confers stronger neuronal and vascular protection compared to VEGF neutralization in a mouse model of retinal vein occlusion

et al. 2023

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PurposeRetinal vein occlusion (RVO) is a sight-threatening condition typically treated with intravitreal injection of vascular endothelial growth factor (VEGF) antagonists. Treatment response to anti-VEGF therapies is highly variable, with poor visual outcomes and treatment response in patients with significant retinal nonperfusion following RVO. Recently, caspase-9 has been identified as a potent regulator of edema, gliosis, and neuronal dysfunction during acute retinal hypoxia. The purpose of this study was to compare the therapeutic effect of caspase-9 inhibition against VEGF-neutralization in an established mouse model of RVO.MethodsAdult male C57Bl/6 J mice were randomized to induction of RVO and treatment with either vehicle, intravitreal injection of anti-VEGF antibody, topical administration of a selective caspase-9 inhibitor (Pen1-XBir3), or a combination therapy. Animals were followed on days 1, 2, and 8 after RVO with fundus retinal imaging, and with optical coherence tomography (OCT) to capture retinal swelling, capillary nonperfusion (measured by disorganization of retinal inner layers, DRIL), hyperreflective foci (HRF), and retinal atrophy. Focal electroretinography (ERG) measurements were performed on day 7. Histology was performed on retinal sections from day 8.ResultsBoth VEGF neutralization and caspase-9 inhibition showed significant retinal protection from RVO compared to vehicle treatment arm. Retinal reperfusion of occluded veins was accelerated in eyes receiving caspase-9 inhibitor, but not significantly different from vehicle in the anti-VEGF group. Retinal edema was suppressed in all treatment groups, with approximately 2-fold greater edema reduction with caspase-9 inhibition compared to VEGF neutralization. HRF were reduced similarly across all treatment groups compared to vehicle. Retinal detachment was reduced only in eyes treated with caspase-9 inhibitor monotherapy. Caspase-9 inhibition reduced retinal atrophy and preserved ERG response; VEGF neutralization did not prevent neurodegeneration following RVO.ConclusionCaspase-9 inhibition confers stronger neuronal and vascular protection compared to VEGF neutralization in the mouse laser-induced model of RVO.

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Section: Resultsmentioning

confidence: 99%

“…Detailed OCT imaging and analysis protocols for the RVO model are described in ( Chen et al, 2022 ).…”

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Caspase-9 inhibition confers stronger neuronal and vascular protection compared to VEGF neutralization in a mouse model of retinal vein occlusion

et al. 2023

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“…FFA has been extensively used as a diagnostic and research tool in clinical and experimental settings [251,258,259]. The small molecular weight and high degree of fluorescence allow the NaFluo dye to pass more readily across barriers than large molecular weight tracers, hence serving as a rapid and sensitive indicator of impaired CNS barriers for early detection of localized vascular leakage and sites of retinal vein occlusion [253,260]. In addition, this technique is cost effective and non-toxic as the dye is eliminated in urine within 24-36 h of administration [261].…”

Section: Assessment Of Brb Leakagementioning

confidence: 99%

“…In addition, this technique is cost effective and non-toxic as the dye is eliminated in urine within 24-36 h of administration [261]. However, despite its many advantages, quantification of conventional fluorescein images is limited by the lack of accurate timing, reproducibility between studies and limited information regarding precise leakage location due to lack of depth resolution [253,260]. Another technical limitation is the restricted retinal field of view.…”

Section: Assessment Of Brb Leakagementioning

confidence: 99%

Assessment of Inner Blood–Retinal Barrier: Animal Models and Methods

Bora,

Kushwah,

Maurya

et al. 2023

Cells

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Proper functioning of the neural retina relies on the unique retinal environment regulated by the blood–retinal barrier (BRB), which restricts the passage of solutes, fluids, and toxic substances. BRB impairment occurs in many retinal vascular diseases and the breakdown of BRB significantly contributes to disease pathology. Understanding the different molecular constituents and signaling pathways involved in BRB development and maintenance is therefore crucial in developing treatment modalities. This review summarizes the major molecular signaling pathways involved in inner BRB (iBRB) formation and maintenance, and representative animal models of eye diseases with retinal vascular leakage. Studies on Wnt/β-catenin signaling are highlighted, which is critical for retinal and brain vascular angiogenesis and barriergenesis. Moreover, multiple in vivo and in vitro methods for the detection and analysis of vascular leakage are described, along with their advantages and limitations. These pre-clinical animal models and methods for assessing iBRB provide valuable experimental tools in delineating the molecular mechanisms of retinal vascular diseases and evaluating therapeutic drugs.

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Exploring laser-induced acute and chronic retinal vein occlusion mouse models: Development, temporal in vivo imaging, and application perspectives

Xu,

Li,

Tang

et al. 2024

PLoS ONE

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Photodynamic venous occlusion is a commonly accepted method for establishing mouse models of retinal vein occlusion (RVO). However, existing model parameters do not distinguish between acute and chronic RVO subtypes. Large variations in laser energy seem to correlate with fluctuating retinopathy severity and high rates of venous recanalization during the acute phase, along with the variable levels of retinal perfusion during the chronic phase. After optimizing the modeling procedure and defining success and exclusion criteria, laser energy groups of 80mW, 100mW, and 120mW were established. Multimodal imaging confirmed that higher energy levels increased the incidence of retinal cystoid edema and intraretinal hemorrhage, exacerbated the severity of exudative retinal detachment, and reduced the venous recanalization rate. For the acute model, 100mW was considered an appropriate parameter for balancing moderate retinopathy and venous recanalization. Continuous imaging follow-up revealed that day 1 after RVO was the optimal observation point for peaking of retinal thickness and intensive occurrence of retinal cystic edema and intraretinal hemorrhage. After excluding the influence of venous recanalization on retinal thickness, acute retinal edema demonstrated a positive response to standard anti-vascular endothelial growth factor therapy, validating the clinical relevance of the acute RVO model for further study in pathogenic mechanisms and therapeutic efficacy. For the chronic model, the 120mW parameter with the lowest venous recanalization rate was applied, accompanied by an increase in both photocoagulation shots and range to ensure sustained vein occlusion. Imaging follow-up clarified non-ischemic retinopathy characterized by tortuosity and dilation of the distal end, branches, and adjacent veins of the occluded vein. These morphological changes are quantifiable and could be combined with electrophysiological functional assessment for treatment effectiveness evaluation. Moreover, the stable state of venous occlusion may facilitate investigations into response and compensation mechanisms under conditions of chronic retinal hypoperfusion.

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<em>In Vivo</em> Vascular Injury Readouts in Mouse Retina to Promote Reproducibility

Cited by 3 publications

References 27 publications

Caspase-9 inhibition confers stronger neuronal and vascular protection compared to VEGF neutralization in a mouse model of retinal vein occlusion

Caspase-9 inhibition confers stronger neuronal and vascular protection compared to VEGF neutralization in a mouse model of retinal vein occlusion

Assessment of Inner Blood–Retinal Barrier: Animal Models and Methods

Exploring laser-induced acute and chronic retinal vein occlusion mouse models: Development, temporal in vivo imaging, and application perspectives

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