Retinal Pigment Epithelial Cells Reduce Vascular Leak and Proliferation in Retinal Neovessels

Academic Background

Retinal pigment epithelial cells (RPE cells) play a crucial role in various functions of the retina, including responding to stress and damage in the neuroretina. In many neurodegenerative diseases, such as age-related macular degeneration (AMD), retinitis pigmentosa, and macular telangiectasia type 2 (MacTel), RPE cells proliferate and migrate into the neuroretina, forming intraretinal pigment plaques. Although these pigmentary changes are hallmarks of disease progression, it remains unclear whether their presence is protective or detrimental.

This study aims to investigate the impact of pigment plaques on vascular changes and disease progression in MacTel and to explore the underlying pathological mechanisms using animal models. The hypothesis is that the proliferation, migration, and perivascular accumulation of RPE cells may stabilize vascular proliferation and reduce vascular permeability, thereby exerting a protective effect on the diseased retina.

Source of the Paper

This paper is co-authored by Simone Tzaridis, Edith Aguilar, Michael I. Dorrell, Martin Friedlander, and Kevin T. Eade, affiliated with the Lowy Medical Research Institute, The Scripps Research Institute, and Point Loma Nazarene University. The paper was published in 2025 in the journal Angiogenesis.

Research Process and Results

Research Process

1. Clinical Study:
   The study first conducted a retrospective longitudinal analysis of multimodal retinal images from MacTel patients to evaluate the impact of pigment plaques on vascular changes and disease progression. The study included 1,216 eyes from 608 patients, with 69 eyes analyzed over an observation period of 24 to 60 months. Imaging techniques such as fundus fluorescein angiography (FFA) and optical coherence tomography (OCT) were used to assess the relationship between pigment plaque formation and vascular leakage and neovascular growth.

2. Animal Model Study:
   The study used the very-low-density lipoprotein receptor mutant mouse (Vldlr−/− mouse) as an animal model for MacTel. Through immunofluorescence, gene expression analysis, and pharmacological interventions, the study investigated the epithelial-mesenchymal transition (EMT) of RPE cells and its effects on vascular leakage and neovascular growth.

Key Findings

1. Relationship Between Pigment Plaques and Vascular Leakage:
   In MacTel patients, the accumulation of perivascular pigment plaques was associated with reduced vascular leakage and stabilized neovascular growth. The study found that vessels covered by pigment plaques exhibited decreased leakage in both early and late phases of FFA, suggesting that the pigment plaques have a sealing effect on the vessels rather than merely casting a shadow.

2. EMT of RPE Cells:
   In the Vldlr−/− mouse model, RPE cells underwent EMT during proliferation and migration. Gene expression analysis revealed significant upregulation of EMT-related genes (e.g., Snail1/2, Vimentin, Fibronectin) in RPE cells, while epithelial markers (e.g., E-cadherin, ZO-1) were downregulated.

3. Impact of EMT Inhibition:
   Pharmacological inhibition of EMT in Vldlr−/− mice led to increased vascular leakage and neovascular growth, while the accumulation of pigment plaques decreased. This indicates that EMT and perivascular accumulation of RPE cells have a protective effect on stabilizing neovascularization and reducing vascular leakage.

Conclusions and Significance

The findings suggest that the proliferation, migration, and perivascular accumulation of RPE cells can stabilize neovascular growth and reduce vascular leakage, thereby exerting a protective effect on the diseased retina. This discovery changes our understanding of the role of pigment plaques in retinal diseases and implies that interfering with this “natural repair mechanism” may have detrimental effects on disease progression, and such interventions should be avoided.

Research Highlights

1. Key Discovery:
   The study is the first to reveal the protective role of RPE cells in MacTel, showing that the accumulation of pigment plaques can reduce vascular leakage and stabilize neovascular growth.

2. Methodological Innovation:
   The study combined clinical retrospective research with animal model experiments, using multimodal imaging and gene expression analysis to explore the EMT of RPE cells and its impact on vascular changes.

3. Application Value:
   The findings provide new insights for the treatment of MacTel and other retinal diseases, suggesting that interventions should avoid disrupting the natural repair mechanisms of RPE cells.

Other Valuable Information

The study also found that the formation of pigment plaques may be locally triggered by vascular leakage and proliferation, indicating that pigment plaques could serve as biomarkers for predicting neovascular exudation and vascular stabilization. Future prospective longitudinal studies will further validate these findings.

Conclusion

Through detailed clinical and experimental research, this study reveals the protective role of RPE cells in retinal diseases, offering new perspectives and strategies for the treatment of related conditions.