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Impact of phlebotomy induced anemia on whole retinal transcriptome at P15 and P20 in the rat 50/10 OIR model

ABSTRACT: Phlebotomy-induced-anemia (PIA), which induces tissue hypoxia and angiogenesis, occurs universally among infants at risk for severe retinopathy of prematurity (ROP). We hypothesized that PIA exacerbates pathologic retinal neovascularization in ROP. Methods: We induced PIA to a hematocrit of 18% among rats undergoing the established 50/10 oxygen-induced retinopathy (OIR) model. Rats were euthanized at P15 and P20, during the avascular and neovascular phases of OIR, respectively. Whole retinal transcriptomes were compared to non-PIA controls. Results: RNA sequencing showed dampened pathways of angiogenesis, inflammation, and neural development in anemic OIR females at P20. Conclusion: PIA dampened transcriptomic pathways central to retinal vascular and neural development in neonatal rats. These data suggest PIA provides a protective effect from ROP.

ORGANISM(S): Rattus norvegicus

PROVIDER: GSE272252 | GEO | 2024/09/04

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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Impact of phlebotomy induced anemia on whole retinal transcriptome at P15 and P20 in the rat 50/10 OIR model

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