Targeting endothelial ERG to mitigate vascular regression in retinopathies

• 成果类型: Article
• 署名作者: Ma, Eric; Schafer, Christopher M.; Xie, Jun; Rudenko, Yelyzaveta; Knapp, John T. H.; Randi, Anna M.; Birdsey, Graeme M.; Griffin, Courtney T.
• 署名单位: Oklahoma Medical Research Foundation; Imperial College London; University of Oklahoma System; University of Oklahoma Health Sciences Center; University of Central Oklahoma
• 刊物名称: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
• ISSN/ISSBN: 0027-8679
• DOI: 10.1073/pnas.2507194122
• 发表日期: 2025-09-30
• 关键词: oxygen-induced retinopathy; angiogenesis; MODEL; hyperoxia; insights; retina; GROWTH; mouse; fli1

摘要

Retinopathy of prematurity (ROP) and diabetic retinopathy (DR) are ocular disorders in which an initial loss of retinal capillaries leads to damaging tissue ischemia followed by a compensatory neovascularization response that generates pathological capillaries in the eye. Using a mouse model of ROP and samples from DR patients, we found that the highly homologous and homeostatic erythroblast transformation-specific (ETS) family transcription factors ETS-related gene (ERG) and Friend leukemia integration 1 (FLI1) are downregulated in endothelial cells (ECs) of retinal capillaries prior to their regression in early stages of these diseases. We developed a mouse model of inducible EC-specific overexpression of Erg and found it mitigates capillary regression, retinal neuron death, neovascularization, and visual defects in the ROP model. Erg overexpression also reduces capillary regression in early stages of a murine DR model. We next found that simultaneous deletion of endothelial Erg and Fli1 is sufficient to promote regression of the pathological retinal capillaries that arise in late stages of the ROP model. Altogether, our data demonstrate that deletion of homeostatic endothelial ETS factors promotes capillary regression, while maintenance of even one of these factors prevents regression. These findings offer insights into approaches for preventing and treating retinopathies at different stages of these diseases.