Retinal pigment epithelial cells reduce vascular leak and proliferation in retinal neovessels

Abstract Retinal pigment epithelial (RPE)-cells possess numerous functions and may respond to stress and damage of the neuroretina. In different neurodegenerative diseases, including age-related macular degeneration (AMD), retinitis pigmentosa, and macular telangiectasia type 2 (MacTel), RPE-cells have been shown to proliferate and migrate into the neuroretina, forming intraretinal pigment plaques. Though pigmentary changes are associated with disease progression, it is not known if their presence is protective or detrimental. In this study, we evaluated the impact of pigment plaques on vascular changes and disease progression in patients with macular telangiectasia type 2 (MacTel), an example of a progressive neurodegenerative retinal disease. We then studied underlying pathomechanisms using a mouse model mirroring these changes, the very-low-density lipoprotein receptor mutant (Vldlr–/–) mouse. In a retrospective, longitudinal study, we analyzed multimodal retinal images of patients with MacTel and showed that pigment plaques were associated with a decrease in vascular leakage and stabilized neovascular growth. Using genetic approaches, we analyzed changes in expression levels of relevant genes in the RPE and retinas of Vldlr-/- mice during RPE-proliferation and migration. Our data indicated that RPE-cells transitioned from an epithelial to a mesenchymal state (“epithelial-mesenchymal transition”, EMT), proliferated and accumulated along neovessels. Using dextran angiography and immunofluorescence, we demonstrated that the perivascular accumulation of RPE-cells reduced vascular leakage. Pharmacologic inhibition of EMT led to a decrease in pigment coverage and exacerbation of neovascular growth and exudation. Our findings indicate that the proliferation, migration and perivascular accumulation of RPE-cells may stabilize vascular proliferation and exudation, thereby exerting a protective effect on the diseased retina. We conclude that interfering with this “natural repair mechanism” may have detrimental effects on the course of the disease and should thus be avoided. Competing Interest Statement The authors have declared no competing interest. Funding Statement This research was funded by The Lowy Medical Research Institute, La Jolla, CA, USA. Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: The ethics committees/IRBs listed below gave ethical approval for this work: Comite consultatif de protection des personnes dans la recherche biomedicale (CCPPRB); Human Research Ethics Committee (HREC); London City Road & Hampstead Research Ethics Committee; Sterling Institutional Review Board; Ethik-Kommission der Aerztekammer Westfalen-Lippe und der Medizinischen Fakultaet der WWU Muenster; The State of Israel Ministry of Health The Chaim Sheba Medical Center; Ethik-Kommission - Medizinische Fakultaet Bonn; University of Pennsylvania Institutional Review Board; Kantonale Ethikkommission Bern (KEK); University of Miami Human Subject Research Office. I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes Data Availability All data produced in the present work are contained in the manuscript.