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Proliferative diabetic retinopathy subtypes defined by immune defense and endothelial mitochondrial dysfunction

ABSTRACT: Proliferative diabetic retinopathy (PDR) is a major complication of diabetes characterized by pathological angiogenesis in the retina. Standard treatment includes vitrectomy to remove these abnormal vessels, and the resulting clinical specimens provide an opportunity to define drivers of PDR. Here, we profiled endothelial and immune cells from such samples to identify disease mechanisms. In some patients, endothelial cells were more abundant, whereas in others, immune cells predominated. Immune cells exhibit gene expression programs directed against pathological endothelium, suggesting an endogenous defense that may explain the scarcity of endothelial cells in certain cases. Preoperative anti-vascular endothelial growth factor (VEGF) therapy altered transcriptional programs in both endothelial and immune cells, indicating that its effects extend beyond the vasculature. A comparison of endothelial signatures from PDR patients and nondiabetic donor retinas revealed a distinct molecular program in PDR, prominently marked by mitochondrial dysfunction. In contrast, endothelial cells from the murine oxygen-induced retinopathy (OIR) model lacked mitochondrial dysfunction, although other features of pathological angiogenesis were shared. These findings suggest that PDR is not a uniform disease but comprises distinct types characterized by either immune-mediated clearance of pathological vessels or endothelial mitochondrial dysfunction. They also revealed that anti-VEGF therapy influences both endothelial and immune compartments, with implications for treatment strategies. Finally, the data clarify both the relevance and limitations of the OIR model for preclinical testing of new therapeutic targets.

ORGANISM(S): Homo sapiens

PROVIDER: GSE307925 | GEO | 2025/09/19

REPOSITORIES: GEO

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Project description:Background: Retinal neovascularization (RNV) as a result of retinal ischemia, such as in proliferative diabetic retinopathy (PDR) and retinopathy of prematurity (ROP), can lead to vitreous hemorrhage, tractional retinal detachment, and irreversible loss of vision if left untreated. Although panretinal laser photocoagulation and anti-vascular endothelial growth factor (VEGF) injections are efficient treatment modalities, a significant number of patients do not respond to either treatment. This clinical finding suggests that other, previously unrecognized mediators and signaling pathways may contribute to RNV development and could represent valuable targets for future treatments. Methods: In search of phylogenetically conserved angiogenic mediators, we examined the transcriptional profile of murine RNV from C57BL/6J mice (n=14) in the oxygen-induced retinopathy (OIR) model as well as human RNV membranes from PDR patients (n=7), who had undergone vitrectomy and compared them with corresponding control tissues (n=13, 10 respectively). Genes that were differentially expressed (DEGs) between RNV and control samples were identified for human and murine samples and their associated gene ontology (GO) clusters analyzed. Lastly, human and murine DEGs were compared to identify phylogenetically conserved factors. Findings: Transcriptional profiles of murine RNV showed that DEGs linked to the activation of the innate immune system (Msn, Cd34), extracellular matrix organisation (Col4a1, Gfap), and regulation of angiogenesis (Col4a2, Fgf2) were significantly upregulated both at the ischemic, preproliferative stage of the disease (OIR p14) as well as at the proliferative stage (OIR p17). While similar GO terms were upregulated in human RNV, only a small overlap in DEGs between both species was detected. Phylogenetically conserved mediators upregulated in both murine and human RNV included ANGPT2, S100A8, MCAM, EDNRA, MRC1, and CCR7. Interpretation: This study identifies phylogenetically conserved inflammatory and pro-angiogenic mediators that are significantly upregulated in both murine and human RNV. Among them, MCAM, ENDRA and MRC1 emerged as the most upregulated, phylogenetically conserved DEGs not yet implicated in human RNV, thus representing potential new treatment targets for ischemic retinal diseases.

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Proliferative diabetic retinopathy subtypes defined by immune defense and endothelial mitochondrial dysfunction

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