Erythropoietin as a Retinal Angiogenic Factor in Proliferative Diabetic Retinopathy

Watanabe, Dai; Suzuma, Kiyoshi; Matsui, Shigeyuki; Kurimoto, Masafumi; Kiryu, Junichi; Kita, Mihori; Suzuma, Izumi; Ohashi, Hirokazu; Ojima, T.; Murakami, Tomoaki; Kobayashi, Toshihiro; Masuda, Seiji; Nagao, Masaya; Yoshimura, Nagahisa; Takagi, Hitoshi

doi:10.1056/nejmoa041773

Cited by 450 publications

(347 citation statements)

References 38 publications

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“…The side effects of rhEPO in very preterm infants have drawn much concern, especially because rhEPO has been reported to promote angiogenesis and ROP 47. However, studies in the current literature show conflicting results with regard to ROP being associated with the use of rhEPO in preterm infants 17, 20, 22, 23, 48.…”

Section: Discussionmentioning

confidence: 99%

Recombinant human erythropoietin improves neurological outcomes in very preterm infants

Shi

Sun

et al. 2016

Annals of Neurology

115

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ObjectiveTo evaluate the efficacy and safety of repeated low‐dose human recombinant erythropoietin (rhEPO) in the improvement of neurological outcomes in very preterm infants.MethodsA total of 800 infants of ≤32‐week gestational age who had been in an intensive care unit within 72 hours after birth were included in the trial between January 2009 and June 2013. Preterm infants were randomly assigned to receive rhEPO (500IU/kg; n = 366) or placebo (n = 377) intravenously within 72 hours after birth and then once every other day for 2 weeks. The primary outcome was death or moderate to severe neurological disability assessed at 18 months of corrected age.ResultsDeath and moderate/severe neurological disability occurred in 91 of 338 very preterm infants (26.9%) in the placebo group and in 43 of 330 very preterm infants (13.0%) in the rhEPO treatment group (relative risk [RR] = 0.40, 95% confidence interval [CI] = 0.27–0.59, p < 0.001) at 18 months of corrected age. The rate of moderate/severe neurological disability in the rhEPO group (22 of 309, 7.1%) was significantly lower compared to the placebo group (57 of 304, 18.8%; RR = 0.32, 95% CI = 0.19–0.55, p < 0.001), and no excess adverse events were observed.InterpretationRepeated low‐dose rhEPO treatment reduced the risk of long‐term neurological disability in very preterm infants with no obvious adverse effects. Ann Neurol 2016;80:24–34

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Section: Discussionmentioning

confidence: 99%

Recombinant human erythropoietin improves neurological outcomes in very preterm infants

Shi

Sun

et al. 2016

Annals of Neurology

115

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“…Under normoxia, the retinal vasculature of these mice is similar to that of wild type mice. However, in mice exposed to the oxygen-induced retinopathy paradigm, EPO mRNA (in contrast to VEGF mRNA) is reduced during the post-oxygen exposure phase and retinal vascularization is almost completely suppressed (Watanabe et al, 2005). Likewse, intraperitoneal injection of EPO into the HLF +/− mice increased the formation of neovascular tufts.…”

Section: Erythropoietin (Epo)-epomentioning

confidence: 96%

“…Other evidence comes from clinical studies showing increased vitreous EPO levels in diabetic retinopathy compared to non-diabetic retina (Watanabe et al, 2005). Preterm infants are often treated with EPO to prevent anemia.…”

Section: Erythropoietin (Epo)-epomentioning

confidence: 99%

Vascular endothelial growth factor in eye disease

Penn

Madan

Caldwell

et al. 2008

Progress in Retinal and Eye Research

612

527

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Collectively, angiogenic ocular conditions represent the leading cause of irreversible vision loss in developed countries. In the U.S., for example, retinopathy of prematurity, diabetic retinopathy and age-related macular degeneration are the principal causes of blindness in the infant, working age and elderly populations, respectively. Evidence suggests that vascular endothelial growth factor (VEGF), a 40 kDa dimeric glycoprotein, promotes angiogenesis in each of these conditions, making it a highly significant therapeutic target. However, VEGF is pleiotropic, affecting a broad spectrum of endothelial, neuronal and glial behaviors, and confounding the validity of anti-VEGF strategies, particularly under chronic disease conditions. In fact, among other functions VEGF can influence cell proliferation, cell migration, proteolysis, cell survival and vessel permeability in a wide variety of biological contexts. This article will describe the roles played by VEGF in the pathogenesis of retinopathy of prematurity, diabetic retinopathy and age-related macular degeneration. The potential disadvantages of inhibiting VEGF will be discussed, as will the rationales for targeting other VEGF-related modulators of angiogenesis.

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“…46 However, studies have described that VEGF alone does not complete angiogenesis, thus search for other angiogenic factors that are equally contributing to angiogenesis has unraveled the involvement of EPO. 47,48 Angiogenesis is caused by the activation of HIF-1α, under hypoxic conditions, promotes expression of VEGF transcript. 34 At the same time, regulation of EPO is also mediated by the control of HIF-1α.…”

Section: The Role Of Epo In the Eyementioning

confidence: 99%

“…Its role in angiogenesis causing neovascularization is a dreaded occurrence in the eye. 48 Ischemia induces increased concentration of EPO, which stimulates proliferation, 45 migration, 45 and angiogenesis 47,48 in endothelial cells that express EPOR. 45,46,71 Late treatment with EPO has been shown to induce pathological neovascularization in proliferative DR and advanced stage of retinopathy of prematurity.…”

Section: Application Of Epo Therapy For Ocular Disordersmentioning

confidence: 99%

Revisiting the role of erythropoietin for treatment of ocular disorders

Ding

Leow

Munisvaradass

et al. 2016

Eye

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Erythropoietin (EPO) is a glycoprotein hormone conventionally thought to be responsible only in producing red blood cells in our body. However, with the discovery of the presence of EPO and EPO receptors in the retinal layers, the EPO seems to have physiological roles in the eye. In this review, we revisit the role of EPO in the eye. We look into the biological role of EPO in the development of the eye and the physiologic roles that it has. Apart from that, we seek to understand the mechanisms and pathways of EPO that contributes to the therapeutic and pathological conditions of the various ocular disorders such as diabetic retinopathy, retinopathy of prematurity, glaucoma, age-related macular degeneration, optic neuritis, and retinal detachment. With these understandings, we discuss the clinical applications of EPO for treatment of ocular disorders, modes of administration, EPO formulations, current clinical trials, and its future directions.

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Erythropoietin as a Retinal Angiogenic Factor in Proliferative Diabetic Retinopathy

Abstract: Our data suggest that erythropoietin is a potent ischemia-induced angiogenic factor that acts independently of VEGF during retinal angiogenesis in proliferative diabetic retinopathy.

Cited by 450 publications

References 38 publications

Recombinant human erythropoietin improves neurological outcomes in very preterm infants

Recombinant human erythropoietin improves neurological outcomes in very preterm infants

Vascular endothelial growth factor in eye disease

Revisiting the role of erythropoietin for treatment of ocular disorders

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