Silicone Wire Embolization-induced Acute Retinal Artery Ischemia and Reperfusion Mouse Model: Transcriptomic Insights into Pathological Processes

Core Concepts

The UPOAO mouse model effectively simulates the characteristic features of retinal artery occlusion, including impaired visual function, retinal neural cell loss, and structural changes. Transcriptomic analysis reveals distinct pathophysiological processes related to immune cell migration, oxidative stress, and immune inflammation during ischemia and reperfusion periods.

Abstract

The study aimed to develop a mouse model that can accurately simulate the pathological processes of retinal artery occlusion (RAO). The researchers established a unilateral pterygopalatine ophthalmic artery occlusion (UPOAO) mouse model by combining silicone wire embolization and carotid artery ligation to block the blood supply to the retina. Key highlights: The UPOAO model successfully replicated the acute interruption of retinal blood supply seen in RAO patients. A 60-minute ischemia duration led to major retinal neural cell loss and visual function impairment. Histological examination showed notable thinning of the inner retinal layers, especially the ganglion cell layer. Temporal transcriptome analysis revealed pathophysiological processes related to immune cell migration, oxidative stress, and immune inflammation during ischemia and reperfusion periods. Resident microglia and peripheral leukocytes showed pronounced increases during reperfusion. Comparison with other ischemia-reperfusion models (HIOP and UCCAO) highlighted unique enrichments in lipid and steroid metabolism-related genes in the UPOAO model. The UPOAO model provides a novel tool for screening pathogenic genes and promoting further therapeutic research in RAO.

Stats

Retinal ganglion cell density decreased significantly after 60 minutes of ischemia and 3 or 7 days of reperfusion. The b-wave amplitude in electroretinography (ERG) notably declined after 60 minutes of ischemia and 3 days of reperfusion, and further decreased by 50% compared to sham eyes at 7 days of reperfusion. The amplitudes of oscillatory potentials (OPs) in ERG decreased to less than 50% of sham eyes in the 60-minute ischemia and 7-day reperfusion group. The thickness of the inner retinal layers, especially the ganglion cell layer, showed notable thinning after UPOAO.

Quotes

"The UPOAO model successfully replicated the acute interruption of retinal blood supply seen in RAO patients." "Temporal transcriptome analysis revealed various pathophysiological processes related to immune cell migration, oxidative stress, and immune inflammation during non-reperfusion and reperfusion periods." "Comparison of differentially expressed genes between the UPOAO and high intraocular pressure models identified specific enrichments in lipid and steroid metabolism-related genes in the UPOAO model."

Key Insights Distilled From

Silicone Wire Embolization-induced Acute Retinal Artery Ischemia and Reperfusion Model in Mouse: Gene Expression Provide Insight into Pathological Processes

by Wang,Y., Li,... at www.biorxiv.org 05-01-2024

https://www.biorxiv.org/content/10.1101/2024.05.01.592074v1

Deeper Inquiries

How could the insights from the UPOAO model be leveraged to develop novel neuroprotective therapies for retinal ischemic diseases?

The UPOAO model provides a valuable platform for studying the pathophysiological processes of retinal ischemia and reperfusion injury, particularly in the context of retinal artery occlusion (RAO). By accurately replicating the acute interruption of blood supply to the retina, this model allows researchers to investigate the effects of ischemia on major retinal neural cells, such as retinal ganglion cells (RGCs), bipolar cells (BCs), horizontal cells (HCs), and cholinergic amacrine cells. Understanding the mechanisms underlying the loss of these neural cells and the subsequent visual impairment can guide the development of neuroprotective therapies for retinal ischemic diseases. One potential application of the UPOAO model is in screening and testing neuroprotective agents that can mitigate the damage caused by retinal ischemia. By evaluating the survival of retinal neural cells and visual function in response to different durations of ischemia and reperfusion, researchers can identify potential therapeutic targets and pathways for intervention. For example, the observed changes in immune cell migration, oxidative stress, and inflammation highlight key processes that could be targeted by neuroprotective agents to prevent cell death and preserve retinal function. Furthermore, the UPOAO model can be used to investigate the role of lipid and steroid metabolism in the pathogenesis of retinal ischemia-reperfusion injury. The identification of specific enrichments in genes related to these metabolic pathways suggests that targeting lipid and steroid metabolism could offer novel therapeutic strategies for treating retinal ischemic diseases. By elucidating the mechanisms by which these metabolic pathways contribute to retinal damage, researchers can develop targeted interventions to protect against ischemic injury and promote retinal cell survival. In summary, the insights gained from the UPOAO model can inform the development of novel neuroprotective therapies for retinal ischemic diseases by identifying key pathophysiological processes, potential therapeutic targets, and metabolic pathways that contribute to retinal damage.

What are the potential limitations of the UPOAO model in fully recapitulating the complex pathophysiology of retinal artery occlusion in humans?

While the UPOAO model offers valuable insights into the pathophysiology of retinal ischemia and reperfusion injury, there are several limitations to consider in its ability to fully recapitulate the complex pathophysiology of retinal artery occlusion (RAO) in humans. Simplified Model: The UPOAO model focuses on acute interruption of blood supply to the retina through silicone wire embolization and carotid artery ligation. This simplified approach may not fully capture the multifactorial nature of RAO in humans, which can involve various underlying vascular, inflammatory, and metabolic factors. Species Differences: Mice and humans have distinct anatomical and physiological differences in their retinal structure and vascular supply. The response to ischemia and reperfusion injury may vary between species, limiting the direct translation of findings from the UPOAO model to human RAO. Duration of Ischemia: While the UPOAO model allows for the investigation of different durations of ischemia and reperfusion, the optimal ischemic duration in mice may not directly correlate with the clinical course of RAO in humans. The time course of retinal damage and functional impairment may differ between the model and human patients. Cellular Complexity: The UPOAO model primarily focuses on the survival of major retinal neural cells, such as RGCs, BCs, HCs, and cholinergic amacrine cells. However, the complex interactions between various retinal cell types, including glial cells, endothelial cells, and immune cells, in the pathogenesis of RAO may not be fully captured in this model. Therapeutic Translation: While the UPOAO model can provide insights into potential neuroprotective therapies for retinal ischemic diseases, the translation of findings from preclinical models to clinical applications in humans requires further validation and testing in human studies. Overall, while the UPOAO model offers a valuable tool for studying retinal ischemia-reperfusion injury, researchers should be mindful of its limitations in fully recapitulating the complex pathophysiology of retinal artery occlusion in humans.

Given the observed changes in lipid and steroid metabolism, how might these metabolic pathways contribute to the pathogenesis of retinal ischemia-reperfusion injury, and could they serve as targets for therapeutic intervention?

The observed changes in lipid and steroid metabolism in the UPOAO model provide valuable insights into the pathogenesis of retinal ischemia-reperfusion injury and suggest potential targets for therapeutic intervention. Lipid and steroid metabolism play crucial roles in maintaining retinal homeostasis, and dysregulation of these pathways can contribute to retinal damage and dysfunction during ischemia-reperfusion injury. Oxidative Stress: Lipid metabolism is closely linked to oxidative stress, a key driver of retinal damage in ischemia-reperfusion injury. Lipids are vulnerable to oxidation, leading to the generation of reactive oxygen species (ROS) and lipid peroxidation products that can damage retinal cells. Targeting lipid metabolism pathways involved in ROS production could help mitigate oxidative stress and protect against retinal injury. Inflammation: Lipid metabolism also influences the production of inflammatory mediators that contribute to immune responses in the retina. Dysregulated lipid metabolism can lead to the accumulation of lipid mediators that promote inflammation and immune cell activation. Targeting lipid metabolism pathways involved in inflammation could modulate the immune response and reduce retinal inflammation during ischemia-reperfusion injury. Neuroprotection: Steroid hormones, such as glucocorticoids, have neuroprotective effects in the retina and can modulate inflammatory responses and cell survival pathways. Alterations in steroid metabolism during retinal ischemia-reperfusion injury may impact the availability of neuroprotective steroids and their signaling pathways. Targeting steroid metabolism pathways could enhance neuroprotection and promote retinal cell survival in the face of ischemic injury. Therapeutic Targets: The changes in lipid and steroid metabolism pathways identified in the UPOAO model suggest potential targets for therapeutic intervention. Modulating lipid metabolism enzymes, such as those involved in lipid peroxidation or inflammatory lipid mediator production, could offer new treatment strategies for retinal ischemic diseases. Similarly, targeting steroid metabolism pathways to enhance neuroprotection and reduce inflammation may hold promise for developing novel neuroprotective therapies. In conclusion, the alterations in lipid and steroid metabolism pathways observed in the UPOAO model provide valuable insights into the pathogenesis of retinal ischemia-reperfusion injury and offer potential targets for therapeutic intervention. By targeting these metabolic pathways, researchers may develop novel strategies to protect against retinal damage and promote retinal cell survival in ischemic conditions.