Signaling Through the Erythropoietin Receptor Affects Angiogenesis in Retinovascular Disease

Abstract

PURPOSE. Exogenous erythropoietin (EPO) is being considered for tissue protection and angiogenesis in retinal vascular diseases. However, studies are limited by insufficient tools to address signaling effects through the EPO receptor (EPOR). We used a humanized mouse model of hypoactive EPOR signaling to test the hypothesis that EPOR signaling supports angiogenesis in retinovascular diseases. METHODS. Humanized Knockin EPOR mice (hWtEPOR) with hypoactive EPOR signaling were compared to littermate wild-type mice (WT). Postnatal day (p)7 mice of each genotype were exposed to 75% oxygen for five days, followed by 21% oxygen in the oxygen-induced retinopathy model (OIR) and compared to room-air (RA)-raised pups. At time points after OIR, pups were sacrificed, and flat-mounted, lectin-stained retinas were analyzed for central avascular area or intravitreal neovascular area (IVNV). Flashfrozen retinas were analyzed for angiogenic protein (Epo, VEGF, p-Stat3) and gene (Vegfa, Kdr, Epo, Hif1α, Hif2α) expression levels. RESULTS. In OIR, hWtEPOR mice had increased AVA compared with WT at p8, p12, and p17, but there was no difference in IVNV between hWtEPOR and WT mice at p17. Although VEGF and p-STAT3 proteins were increased in WT at p17 OIR, there were no differences in retinal angiogenic factor expression levels between hWtEPOR and WT OIR at p17 despite similar areas of IVNV. CONCLUSIONS. Our data support the hypothesis that EPOR signaling was associated with regrowth of vascularization following oxygen-induced capillary dropout and played a role in intravitreal angiogenesis. Additional study of EPOR signaling regulation on other angiogenic factor pathways may be considered.

Erythropoietin receptor is a risk factor for prognosis: a potential biomarker in lung adenocarcinoma

“…EPOR is present not only in hematopoietic cells but also in non-hematopoietic cells such as neurons [19], endothelial cells [20], skeletal muscle cells [45] and in various tumors such as breast cancer [46] and head and neck cancer [47]. EPOR expression was also detected in lung cancer cell lines such as H838 [48].…”

“…Activation of JAK2 results in the activation of speci c downstream effectors, such as STAT1, STAT3, or STAT5 [13], the signal transducer and activator of transcription 5 (STAT5) usually refers to STAT5A and STAT5B proteins [14], thus activates phosphatidylinositol 3-kinase (PI3K), protein kinase B (AKT), mitogen-activated protein kinase (MAPK) and extracellular signalregulated kinase 1/2 (ERK1/2) [15,16]. EPOR was originally discovered and described in erythroid progenitor cells, but it is also present in non-hematopoietic cells (tissues, organs) such as adipose tissues [17], bone progenitor cells [18], neurons [19], endothelial cells [20] and intestinal tract [21]. It is also widely present in various cancer cells and tumor tissues, such as head and neck squamous cell carcinoma [22], diffuse large B-cell lymphoma [23], rhabdomyosarcoma [24], breast cancer [25], hepatocellular carcinoma…”

Erythropoietin receptor is a risk factor for prognosis: a potential biomarker in lung adenocarcinoma

“…endothelial cells [20], skeletal muscle cells [45] and in various tumors such as breast cancer [46] and head and neck cancer [47]. EPOR expression was also detected in lung cancer cell lines such as H838 [48].…”

“…Activation of JAK2 results in the activation of speci c downstream effectors, such as STAT1, STAT3, or STAT5 [13], the signal transducer and activator of transcription 5 (STAT5) usually refers to STAT5A and STAT5B proteins [14], thus activates phosphatidylinositol 3-kinase (PI3K), protein kinase B (AKT), mitogen-activated protein kinase (MAPK) and extracellular signalregulated kinase 1/2 (ERK1/2) [15,16]. EPOR was originally discovered and described in erythroid progenitor cells, but it is also present in non-hematopoietic cells (tissues, organs) such as adipose tissues [17], bone progenitor cells [18], neurons [19], endothelial cells [20] and intestinal tract [21]. It is also widely present in various cancer cells and tumor tissues, such as head and neck squamous cell carcinoma [22], diffuse large B-cell lymphoma [23], rhabdomyosarcoma [24], breast cancer [25], hepatocellular carcinoma [26] and laryngeal malignancy [27].…”

Relevance of Peptide Homeostasis in Metabolic Retinal Degenerative Disorders: Curative Potential in Genetically Modified Mice

“…Furthermore, PEDF overexpression has also been shown to attenuate VEGF and β-catenin expression ( Park et al, 2011 ). Moreover, EPO signaling has reduced angiogenesis and vascularization following OIR in mice ( Bretz et al, 2020 ). The expression of NPY and substance P has been observed to decrease in the OIR mouse and they do not appear to play any role in neovascularization, which was further validated in the NPY KO mice, where it was found that NPY does, in fact, not take part in vascularization ( Schmid et al, 2012 ).…”