Dataset Information

Enhancing Retinal Endothelial Glycolysis by Inhibiting UCP2 Promotes Physiologic Retinal Vascular Development in a Model of Retinopathy of Prematurity.

ABSTRACT: Purpose:We address the hypothesis that uncoupling protein 2 (UCP2), a cellular glucose regulator, delays physiologic retinal vascular development (PRVD) by interfering with glucose uptake through glucose transporter 1 (Glut1). Methods:In the rat 50/10 oxygen-induced retinopathy (OIR) model, retinal Glut1 and UCP2 were measured and compared to room air (RA)-raised pups at postnatal day 14 (p14). Pups in OIR and RA received intraperitoneal genipin, an UCP2 inhibitor, or control every other day from p3 until p13. Analyses at p14 included avascular/total retinal area (AVA), Western blots of retinal UCP2 and Glut1, and immunostaining of Glut1 in retinal cryosections. Intravitreal neovascular/total retinal area (IVNV) was analyzed at p18, and electroretinograms were performed at p26. Glut1 and phosphorylated VEGFR2 (p-VEGFR2), glucose uptake, adenosine triphosphate (ATP) production, and cell proliferation were measured in human retinal microvascular endothelial cells (hRMVECs) pretreated with genipin or transfected with UCP2siRNA, Glut1siRNA, or control siRNA when incubated with VEGF or PBS. Results:At p14, OIR pups had increased AVA with decreased Glut1 and increased UCP2 in the retina compared to RA retinas. Intraperitoneal genipin increased retinal Glut1 and reduced AVA. Compared to control, treatment with genipin or knockdown of UCP2 significantly increased Glut1, glucose uptake, ATP production, VEGF-induced p-VEGFR2 and cell proliferation in hRMVECs. Knockdown of Glut1 inhibited VEGF-induced p-VEGFR2. Genipin-treated OIR pups with decreased AVA at p14 had reduced IVNV at p18 and increased amplitudes in a- and b-waves at p26. Conclusions:Extending PRVD by increasing retinal endothelial glucose uptake may represent a strategy to prevent severe retinopathy of prematurity and vision loss.

SUBMITTER: Han X

PROVIDER: S-EPMC6892377 | biostudies-literature | 2019 Apr

REPOSITORIES: biostudies-literature

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Enhancing Retinal Endothelial Glycolysis by Inhibiting UCP2 Promotes Physiologic Retinal Vascular Development in a Model of Retinopathy of Prematurity.

Han Xiaokun X Kong Jun J Hartnett M Elizabeth ME Wang Haibo H

Investigative ophthalmology & visual science 20190401 5

<h4>Purpose</h4>We address the hypothesis that uncoupling protein 2 (UCP2), a cellular glucose regulator, delays physiologic retinal vascular development (PRVD) by interfering with glucose uptake through glucose transporter 1 (Glut1).<h4>Methods</h4>In the rat 50/10 oxygen-induced retinopathy (OIR) model, retinal Glut1 and UCP2 were measured and compared to room air (RA)-raised pups at postnatal day 14 (p14). Pups in OIR and RA received intraperitoneal genipin, an UCP2 inhibitor, or control ever ...[more]

PMID: 30995317

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Project description:PURPOSE:Bedside examination of premature infants at risk for retinopathy of prematurity (ROP) is predominantly performed with ophthalmoscopic en face viewing of the retina. While postmortem retinal microstructures have been studied at the vascular-avascular junction, a critical location for pathogenesis of ROP, to date this has not been possible in vivo. Here we present bedside, non-sedated in vivo cross-sectional imaging and analysis of retinal microstructures at the vascular-avascular junction in infants with ROP using handheld spectral-domain optical coherence tomography (SDOCT). DESIGN:Prospective observational study. PARTICIPANTS:Eleven preterm infants consented for research imaging during ROP screening examinations. METHODS:We imaged the vascular-avascular junction in the temporal retina using a SDOCT system (Envisu, Bioptigen Inc., NC) in 18 eyes from 11 preterm infants with zone I or II, stage 0 through 4 ROP. B-scan and en face images were analyzed and compared to historical light micrographs. MAIN OUTCOME MEASURES:SDOCT morphology at the vascular-avascular junction. RESULTS:Multiple bedside SDOCT findings at the vascular-avascular junction were comparable to historic light micrographs: thickened inner retinal ridge structure in stage 2 ROP was comparable to thickened vanguard and rear guard cells in micrographs; vascular tufts on the posterior retinal surface in stage 2 ROP, broad arcs of neovascularization above the retina in stage 3 ROP, and splitting of inner retinal layers into clefts on either side of neovascularization mimicked findings of historic light micrographs. A unique findings was thickening of the avascular inner retinal band adjacent to neovascularization. On SDOCT imaging over several weeks, neovascularization and retinal clefts diminished after intravitreal bevacizumab therapy. CONCLUSIONS:Retinal morphology at the vascular-avascular junction imaged with handheld SDOCT is consistent with known histopathology, and provide the advantage of monitoring change in vivo over time. These unique findings provide new insights into preterm retinal neurovascular development in ROP.

Project description:OBJECTIVE:To determine the effects of oxygen fluctuations on pigment epithelial-derived factor (PEDF) and vascular endothelial growth factor (VEGF)/PEDF ratios in a relevant rat model of retinopathy of prematurity (ROP). METHODS:The expression of retinal PEDF mRNA and of VEGF and PEDF protein were determined using real-time polymerase chain reaction or enzyme-linked immunosorbent assays at different postnatal day ages for rat pups raised in room air (RA) or in a rat model mimicking ROP. Statistical outcomes were determined with factorial analyses of variance. Mean VEGF and PEDF protein levels were determined at different ages for rats in the ROP model and for RA-raised rats, and the ratio of VEGF/PEDF protein versus age was plotted. At postnatal day (P) 14, inner retinal plexus vascularization had extended to the ora serrata in pups raised in RA. In the ROP model, avascular retina persisted at P14 and intravitreous neovascularization developed at P18. Therefore, VEGF and PEDF expression was determined in the ROP model and in RA-raised rat pups at P14 and P18. RESULTS:Older age was associated with increased PEDF mRNA (p<0.001), PEDF protein (p=0.005), and VEGF protein (p=0.005), and VEGF protein (p<0.0001). Exposure to fluctuations of oxygen in the 50/10 oxygen-induced retinopathy model compared to RA was associated with increased PEDF mRNA (p=0.0185), PEDF protein (p<0.0001), or VEGF protein (p<0.0001). The VEGF/PEDF ratio favored angiogenic inhibition (<1.0) before but not on P14, when avascular retina persisted in the ROP model but not in RA. The VEGF/PEDF ratio favored angiogenesis (>1.0) at P14 and P 18 when intravitreous neovascularization occurred in the ROP model. CONCLUSIONS:Increased expression levels of VEGF and PEDF are associated with older postnatal day age or with exposure to fluctuations in oxygen in the 50/10 oxygen-induced retinopathy model compared to RA. PEDF protein more closely associates with avascular retinal features and neovascularization than does VEGF protein or the VEGF/PEDF in the ROP model. Although PEDF has been proposed as a potential treatment in ROP, interventional studies using PEDF in an ROP model to potentially reduce intravitreous neovascularization are required to determine timing, efficacy, and dose of PEDF.

Dataset Information

Enhancing Retinal Endothelial Glycolysis by Inhibiting UCP2 Promotes Physiologic Retinal Vascular Development in a Model of Retinopathy of Prematurity.

Publications

Enhancing Retinal Endothelial Glycolysis by Inhibiting UCP2 Promotes Physiologic Retinal Vascular Development in a Model of Retinopathy of Prematurity.

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