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Mitigation of oxygen-induced retinopathy in α2β1 integrin-deficient mice.
Madamanchi A, Capozzi M, Geng L, Li Z, Friedman RD, Dickeson SK, Penn JS, Zutter MM
(2014) Invest Ophthalmol Vis Sci 55: 4338-47
MeSH Terms: Animals, Animals, Newborn, Cells, Cultured, Disease Models, Animal, Endothelium, Vascular, Ependymoglial Cells, Gene Expression Regulation, Integrin alpha2beta1, Mice, Mice, Inbred C57BL, Microscopy, Fluorescence, Oxygen, Polymerase Chain Reaction, RNA, Retinopathy of Prematurity, Vascular Endothelial Growth Factor A
Show Abstract · Added February 19, 2015
PURPOSE - The α2β1 integrin plays an important but complex role in angiogenesis and vasculopathies. Published GWAS studies established a correlation between genetic polymorphisms of the α2β1 integrin gene and incidence of diabetic retinopathy. Recent studies indicated that α2-null mice demonstrate superior vascularization in both the wound and diabetic microenvironments. The goal of this study was to determine whether the vasculoprotective effects of α2-integrin deficiency extended to the retina, using the oxygen-induced retinopathy (OIR) model for retinopathy of prematurity (ROP).
METHODS - In the OIR model, wild-type (WT) and α2-null mice were exposed to 75% oxygen for 5 days (postnatal day [P] 7 to P12) and subsequently returned to room air for 6 days (P12-P18). Retinas were collected at postnatal day 7, day 13, and day 18 and examined via hematoxylin and eosin and Lectin staining. Retinas were analyzed for retinal vascular area, neovascularization, VEGF expression, and Müller cell activation. Primary Müller cell cultures from WT and α2-null mice were isolated and analyzed for hypoxia-induced VEGF-A expression.
RESULTS - In the retina, the α2β1 integrin was minimally expressed in endothelial cells and strongly expressed in activated Müller cells. Isolated α2-null primary Müller cells demonstrated decreased hypoxia-induced VEGF-A expression. In the OIR model, α2-null mice displayed reduced hyperoxia-induced vaso-attenuation, reduced pathological retinal neovascularization, and decreased VEGF expression as compared to WT counterparts.
CONCLUSIONS - Our data suggest that the α2β1 integrin contributes to the pathogenesis of retinopathy. We describe a newly identified role for α2β1 integrin in mediating hypoxia-induced Müller cell VEGF-A production.
Copyright 2014 The Association for Research in Vision and Ophthalmology, Inc.
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16 MeSH Terms
Mechanisms and management of retinopathy of prematurity.
Hartnett ME, Penn JS
(2013) N Engl J Med 368: 1162-3
MeSH Terms: Animals, Humans, Retinal Vessels, Retinopathy of Prematurity
Added October 9, 2013
1 Communities
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4 MeSH Terms
Mechanisms and management of retinopathy of prematurity.
Hartnett ME, Penn JS
(2012) N Engl J Med 367: 2515-26
MeSH Terms: Animals, Antioxidants, Erythropoietin, Humans, Infant, Newborn, Infant, Premature, Infant, Very Low Birth Weight, Models, Animal, Oxygen, Retinal Vessels, Retinopathy of Prematurity, Vascular Endothelial Growth Factor A
Added October 9, 2013
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12 MeSH Terms
Role of cytosolic phospholipase A(2) in retinal neovascularization.
Barnett JM, McCollum GW, Penn JS
(2010) Invest Ophthalmol Vis Sci 51: 1136-42
MeSH Terms: Animals, Animals, Newborn, Blotting, Western, Cell Proliferation, Cells, Cultured, Cyclooxygenase 2, Dinoprostone, Disease Models, Animal, Endothelium, Vascular, Enzyme Inhibitors, Enzyme-Linked Immunosorbent Assay, Female, Humans, Hypoxia, Infant, Newborn, Male, Oxygen, Phospholipases A2, Cytosolic, Phosphorylation, Rats, Rats, Sprague-Dawley, Retinal Neovascularization, Retinal Neurons, Retinopathy of Prematurity, Vascular Endothelial Growth Factor A, p38 Mitogen-Activated Protein Kinases
Show Abstract · Added October 9, 2013
PURPOSE - To identify and characterize the role of cytosolic phospholipase A(2) (cPLA(2)) in retinal angiogenesis using relevant cell-based assays and a rodent model of retinopathy of prematurity.
METHODS - The phosphorylation states of cPLA(2) and p38 MAP kinase and the expression of COX-2 were assessed by Western blot analysis in rat Müller cells. The activities of PLA(2) enzymes in rat retinal lysates were assessed using a commercially available assay. Prostaglandin E(2) (PGE(2)) and VEGF levels in Müller cell-conditioned medium and in retinal tissue samples were measured by ELISA. Rat retinal microvascular endothelial cell proliferation was measured using a BrdU assay. Efficacy of the cPLA(2) inhibitor CAY10502 was tested using the rat model of oxygen-induced retinopathy (OIR) in which neovascularization (NV) was assessed by computer-assisted image analysis.
RESULTS - In Müller cells, hypoxia increased the phosphorylation of cPLA(2) and p38 MAP kinase by 4-fold and 3-fold respectively. The cPLA(2) inhibitor CAY10502 decreased hypoxia-induced PGE(2) and VEGF levels in Müller cell-conditioned medium by 68.6% (P < 0.001) and 46.6% (P < 0.001), respectively. Retinal cPLA(2) activity peaked 1 day after oxygen exposure in OIR rats. CAY10502 (250 nM) decreased OIR-induced retinal PGE(2) and VEGF levels by 69% (P < 0.001) and 40.2% (P < 0.01), respectively. Intravitreal injection of 100 nM CAY10502 decreased retinal NV by 53.1% (P < 0.0001).
CONCLUSIONS - cPLA(2) liberates arachidonic acid, the substrate for prostaglandin (PG) production by the cyclooxygenase enzymes. PGs can exert a proangiogenic influence by inducing VEGF production and by stimulating angiogenic behaviors in vascular endothelial cells. Inhibition of cPLA(2) inhibits the production of proangiogenic PGs. Thus, cPLA(2) inhibition has a significant influence on pathologic retinal angiogenesis.
1 Communities
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26 MeSH Terms
The development of the rat model of retinopathy of prematurity.
Barnett JM, Yanni SE, Penn JS
(2010) Doc Ophthalmol 120: 3-12
MeSH Terms: Animals, Disease Models, Animal, Humans, Hyperoxia, Infant, Newborn, Oxygen, Rats, Retinal Neovascularization, Retinopathy of Prematurity
Show Abstract · Added October 9, 2013
Retinopathy of prematurity (ROP) is a potentially blinding disease affecting premature infants. ROP is characterized by pathological ocular angiogenesis or retinal neovascularization (NV). Models of ROP have yielded much of what is currently known about physiological and pathological blood vessel growth in the retina. The rat provides a particularly attractive and cost effective model of ROP. The rat model of ROP consistently produces a robust pattern of NV, similar to that seen in humans. This model has been used to study gross aspects of angiogenesis. More recently, it has been used to identify and therapeutically target specific genes and molecular mechanisms involved in the angiogenic cascade. As angiogenesis occurs as a complication of many diseases, knowledge gained from these studies has the potential to impact nonocular angiogenic conditions. This article provides historical perspective on the development and use of the rat model of ROP. Key findings generated through the use of this model are also summarized.
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9 MeSH Terms
Vascular endothelial growth factor in eye disease.
Penn JS, Madan A, Caldwell RB, Bartoli M, Caldwell RW, Hartnett ME
(2008) Prog Retin Eye Res 27: 331-71
MeSH Terms: Diabetic Retinopathy, Eye Diseases, Humans, Infant, Newborn, Macular Degeneration, Neovascularization, Pathologic, Retinopathy of Prematurity, Vascular Endothelial Growth Factor A
Show Abstract · Added October 9, 2013
Collectively, angiogenic ocular conditions represent the leading cause of irreversible vision loss in developed countries. In the US, 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 40kDa 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.
1 Communities
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8 MeSH Terms
High-resolution manganese-enhanced MRI of experimental retinopathy of prematurity.
Berkowitz BA, Roberts R, Penn JS, Gradianu M
(2007) Invest Ophthalmol Vis Sci 48: 4733-40
MeSH Terms: Animals, Animals, Newborn, Apyrase, Calcium Channel Blockers, Diltiazem, Disease Models, Animal, Female, Humans, Infant, Newborn, Magnetic Resonance Imaging, Manganese, Photoreceptor Cells, Vertebrate, Rats, Rats, Sprague-Dawley, Retinal Neovascularization, Retinopathy of Prematurity
Show Abstract · Added October 9, 2013
PURPOSE - To test the hypothesis that in experimental retinopathy of prematurity (ROP), retinal neovascularization (NV) and vessel tortuosity have distinct spatial and temporal links with receptor and postreceptor ion demand.
METHODS - Newborn rats were raised in either room air (controls) or variable oxygen (50%/10% [50/10]). After 14 days, 50/10 rats were recovered in room air until postnatal day (P) 19 or P22. Peripheral retinal NV severity and incidence and panretinal arteriole and venule tortuosity indexes (TI(a), TI(v)) were measured from ADPase-stained retinal wholemounts. Intraretinal ion demand and retinal thickness were measured from high-resolution manganese-enhanced MRI (MEMRI). In separate experiments, intraretinal manganese uptake was also measured in adult rats pretreated with diltiazem, a Ca(2+) channel antagonist.
RESULTS - In 50/10 rats, peripheral retinal NV severity was significantly greater than in controls at P19 and was decreased by P22. Panretinal TI(a) and TI(v) were increased over control values at P19, but only TI(v) decreased by P22. Unlike control retinas at P19 that had a centroperipheral total retinal thickness gradient, 50/10 retinas had similar central and peripheral total retinal thickness. The 50/10 group also demonstrated a correlation between peripheral retinal NV and TI(a) and TI(v). Peripheral intraretinal uptake of manganese was significantly supernormal at P19 and decreased by P22. Increased peripheral intraretinal retinal manganese uptake was associated with peripheral NV severity and panretinal TI(a). In contrast, ion demand of central postreceptor, but not receptor, retina was significantly associated with peripheral NV severity and panretinal TI(a). Panretinal TI(v) was not correlated with intraretinal ion demand in any case. In adult rats, diltiazem suppressed (P < 0.05) intraretinal manganese uptake.
CONCLUSIONS - The present data raise the possibility that altered retinal layer-specific ion demand causes retinal circulation abnormalities in experimental ROP.
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16 MeSH Terms
Pharmacologic and genetic manipulation of MMP-2 and -9 affects retinal neovascularization in rodent models of OIR.
Barnett JM, McCollum GW, Fowler JA, Duan JJ, Kay JD, Liu RQ, Bingaman DP, Penn JS
(2007) Invest Ophthalmol Vis Sci 48: 907-15
MeSH Terms: Animals, Animals, Newborn, Apyrase, Disease Models, Animal, Enzyme Inhibitors, Gene Silencing, Humans, Hydroxamic Acids, Infant, Newborn, Injections, Matrix Metalloproteinase 2, Matrix Metalloproteinase 9, Matrix Metalloproteinase Inhibitors, Mice, Mice, Inbred C57BL, Organic Chemicals, Oxygen, Pyridines, Rats, Rats, Sprague-Dawley, Retina, Retinal Neovascularization, Retinopathy of Prematurity, Vitreous Body
Show Abstract · Added October 9, 2013
PURPOSE - The efficacy of three matrix metalloproteinase (MMP) inhibitors with various selectivities (Ro-31-9790, AG3340, and DPC-A37668) was investigated in a rat model of retinopathy of prematurity, to examine the roles of MMP-2 and -9 in retinal neovascularization. The susceptibilities of MMP-2(-/-) and -9(-/-) mice to preretinal neovascularization were investigated in a mouse model of oxygen-induced retinopathy.
METHODS - Sprague-Dawley newborn rats were exposed to alternating episodes of 50% and 10% oxygen (variable oxygen exposure) to induce retinal neovascularization. Three MMP inhibitors with various selectivity profiles were administered to variable oxygen-exposed rats via local or systemic routes. Antineovascular efficacy was determined in drug-treated versus vehicle-treated rat pups by computerized imaging of adenosine diphosphatase (ADPase)-stained retinal flatmounts. Wild-type C57BL/6J and isogenic MMP-2(-/-) and -9(-/-) mice were exposed to 75% oxygen followed by normoxia. The mice were killed immediately before or after the normoxic exposure, and eyes were either harvested for retinal dissection and flatmounting or were paraffin embedded and sectioned. Retinal vascular area and retinal neovascularization were assessed by adenosine diphosphatase staining of retinal flatmounts and by counting preretinal nuclei of hematoxylin and eosin-stained retinal sections, respectively.
RESULTS - Ro-31-9790, AG3340, and DPC-A37668 had no effect on normal development of the rat retinal vasculature, regardless of dose or route of administration. Intravitreal injection of Ro-31-9790 (broad-spectrum) immediately after variable-oxygen exposure and 2 days after exposure resulted in 78% and 82% inhibition of retinal neovascularization, respectively. AG3340 (MMP-2- and -9-selective inhibitor) and DPC-A37668 (MMP-2-selective inhibitor) resulted in 65% and 52% inhibition, respectively, when administered by intravitreal injection immediately after variable-oxygen exposure. Intraperitoneal injection of 5, 15, and 50 mg/mL AG3340 or DPC-A37668 for 6 days after variable oxygen exposure resulted in 22% to 39% and 0% to 31% inhibition of neovascularization, respectively. AG3340 and DPC-A37668 administered by oral gavage at doses of 3, 10, or 30 mg/mL provided up to 42% and 86% inhibition of neovascularization, respectively. The average vascular areas of retinas from MMP-2(-/-) or -9(-/-) mice at postnatal day 12 were not significantly different from the wild-type control. There was a 75% (P < 0.001) and 44% (P < 0.01) reduction in preretinal neovascularization in oxygen-exposed MMP-2(-/-) and -9(-/-) mice at postnatal day 19, respectively, compared with wild-type control mice.
CONCLUSIONS - The results of this study suggest that MMP-2 plays a predominant role in retinal angiogenesis in both the mouse and rat models of oxygen-induced retinopathy. Furthermore, MMP-2 inhibition may be a viable therapeutic approach for ocular diseases characterized by retinal neovascularization.
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24 MeSH Terms
Specific involvement of SRC family kinase activation in the pathogenesis of retinal neovascularization.
Werdich XQ, Penn JS
(2006) Invest Ophthalmol Vis Sci 47: 5047-56
MeSH Terms: Animals, Blotting, Western, Cattle, Cell Culture Techniques, Disease Models, Animal, Endothelium, Vascular, Enzyme Activation, Enzyme Inhibitors, Fluorescent Antibody Technique, Indirect, Humans, Hypoxia, Immunoprecipitation, Infant, Newborn, Neuroglia, Phosphorylation, RNA, Small Interfering, Rats, Rats, Long-Evans, Rats, Sprague-Dawley, Recombinant Proteins, Retinal Neovascularization, Retinal Vessels, Retinopathy of Prematurity, Vascular Endothelial Growth Factor A, src-Family Kinases
Show Abstract · Added October 9, 2013
PURPOSE - Src family kinases (SFKs) are membrane-attached nonreceptor protein tyrosine kinases that link a variety of extracellular cues to intracellular signal pathways. The purpose of this study was to characterize the roles of SFKs in vascular endothelial growth factor (VEGF)-mediated retinal angiogenesis.
METHODS - Primary rat retinal glial Müller cells and bovine and human retinal microvascular endothelial cells (RMECs) were used in the in vitro studies. A rat model of retinopathy of prematurity (ROP) was used in the in vivo studies.
RESULTS - In vitro, SFKs were essential for hypoxia-induced VEGF expression in Müller cells and for VEGF signaling in RMECs. However, neither process required significant further phosphorylation of the SFK activation loop Tyr416. In vivo, in a rat model of ROP, a pronounced increase of retinal SFK Tyr416 phosphorylation was observed that was specifically associated with pathologic angiogenesis. These retinas also expressed significantly higher levels of VEGF than did those in healthy controls. Immunohistochemical analysis indicated that Müller cells were the major source of the elevated level of phospho-SFK Tyr416. Intravitreous injection of a selective SFK inhibitor, PP2, significantly reduced retinal VEGF and retinopathy in the ROP model, indicating that SFKs acted as important regulators in abnormal retinal angiogenesis.
CONCLUSIONS - Together, these data suggest that SFK activation through a Tyr416-dependent mechanism may be an important factor in the pathogenesis of retinal neovascularization.
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25 MeSH Terms
Proceedings of the Third International Symposium on Retinopathy of Prematurity: an update on ROP from the lab to the nursery (November 2003, Anaheim, California).
Lutty GA, Chan-Ling T, Phelps DL, Adamis AP, Berns KI, Chan CK, Cole CH, D'Amore PA, Das A, Deng WT, Dobson V, Flynn JT, Friedlander M, Fulton A, Good WV, Grant MB, Hansen R, Hauswirth WW, Hardy RJ, Hinton DR, Hughes S, McLeod DS, Palmer EA, Patz A, Penn JS, Raisler BJ, Repka MX, Saint-Geniez M, Shaw LC, Shima DT, Smith BT, Smith LE, Tahija SG, Tasman W, Trese MT
(2006) Mol Vis 12: 532-80
MeSH Terms: Humans, Infant, Newborn, Retinopathy of Prematurity
Show Abstract · Added October 9, 2013
The Third International Symposium on Retinopathy of Prematurity (ROP) was convened with the aim of cross fertilizing the horizons of basic and clinical scientists with an interest in the pathogenesis and management of infants with ROP. Ten speakers in the clinical sciences and ten speakers in the basic sciences were recruited on the basis of their research to provide state of the art talks. The meeting was held November 9, 2003 immediately prior to the American Academy of Ophthalmology meeting; scholarships were provided for outreach to developing countries and young investigators. This review contain the summaries of the 20 platform presentations prepared by the authors and the abstracts of presented posters. Each author was asked to encapsulate the current state of understanding, identify areas of controversy, and make recommendations for future research. The basic science presentations included insights into the development of the human retinal vasculature, animal models for ROP, growth factors that affect normal development and ROP, and promising new therapeutic approaches to treating ROP like VEGF targeting, inhibition of proteases, stem cells, ribozymes to silence genes, and gene therapy to deliver antiangiogenic agents. The clinical presentations included new insights into oxygen management, updates on the CRYO-ROP and ETROP studies, visual function in childhood following ROP, the neural retina in ROP, screening for ROP, management of stage 3 and 4 ROP, ROP in the third world, and the complications of ROP in adult life. The meeting resulted in a penetrating exchange between clinicians and basic scientists, which provided great insights for conference attendees. The effect of preterm delivery on the normal cross-talk of neuroretinal and retinal vascular development is a fertile ground for discovering new understanding of the processes involved both in normal development and in retinal neovascular disorders. The meeting also suggested promising potential therapeutic interventions on the horizon for ROP.
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3 MeSH Terms