13 results on '"Dennison RJ"'
Search Results
2. Wnt signaling mediates pathological vascular growth in proliferative retinopathy.
- Author
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Chen J, Stahl A, Krah NM, Seaward MR, Dennison RJ, Sapieha P, Hua J, Hatton CJ, Juan AM, Aderman CM, Willett KL, Guerin KI, Mammoto A, Campbell M, Smith LE, Chen, Jing, Stahl, Andreas, Krah, Nathan M, Seaward, Molly R, and Dennison, Roberta J
- Published
- 2011
- Full Text
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3. Young Athletes' Concerns About Sport-Related Concussion: The Patient's Perspective.
- Author
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Stein CJ, MacDougall R, Quatman-Yates CC, Myer GD, Sugimoto D, Dennison RJ, and Meehan WP 3rd
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- Adolescent, Brain Concussion etiology, Child, Cross-Sectional Studies, Female, Health Surveys, Humans, Male, Athletes psychology, Athletic Injuries psychology, Attitude to Health, Brain Concussion psychology
- Abstract
Objective: Few studies have examined the experience and concerns of the concussed athlete. The purpose of this study was to identify the most pressing concerns of athletes with concussion., Design: Cross-sectional survey of athletes who presented for evaluation of a new sport-related concussion during an 8-month period., Setting: Tertiary-level sports medicine division of a large academic pediatric medical center., Participants: One hundred twenty one patients (67 male, 54 female) aged 8 to 18 years who had sustained a sport-related concussion participated in the study by responding to "What is the worst thing for you about having a concussion?" on the study questionnaire. Questionnaires were completed in the clinic waiting room before the visit with a provider., Intervention: Inductive content analysis was used to identify themes in the responses to the study question., Main Outcome Measures: Age, sex, sport played at the time of the current injury, history of previous concussion, known contacts with concussion, and subjective report of worst aspect of concussion., Results: Seventy respondents (57.9%) cited symptoms, and 68 (56.2%) reported loss of activity as the worst part of concussion, including 17 (14.0%) who listed both symptoms and loss of activity., Conclusions: Over half of concussed athletes indicate that the most distressing part of the injury is loss of activities, which may result from symptoms of the injury itself and/or the prescribed treatment., Clinical Relevance: Health care providers should not underestimate the degree to which symptoms and loss of activities affect young athletes' general well-being. In addition to the negative impact of concussion symptoms, there is an obvious cost of physical, cognitive, and social activity restrictions for patients recovering from sport-related concussions that should be explicitly addressed.
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- 2016
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4. SOCS3 is an endogenous inhibitor of pathologic angiogenesis.
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Stahl A, Joyal JS, Chen J, Sapieha P, Juan AM, Hatton CJ, Pei DT, Hurst CG, Seaward MR, Krah NM, Dennison RJ, Greene ER, Boscolo E, Panigrahy D, and Smith LE
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- Animals, Blotting, Western, Carcinoma, Lewis Lung blood supply, Carcinoma, Lewis Lung pathology, Cell Proliferation, Endothelium, Vascular cytology, Endothelium, Vascular metabolism, Insulin-Like Growth Factor I genetics, Insulin-Like Growth Factor I metabolism, Integrases metabolism, Male, Melanoma, Experimental blood supply, Melanoma, Experimental pathology, Mice, Mice, Inbred C57BL, Neovascularization, Pathologic etiology, Paraneoplastic Syndromes, Ocular pathology, RNA, Messenger genetics, Real-Time Polymerase Chain Reaction, Reverse Transcriptase Polymerase Chain Reaction, STAT3 Transcription Factor genetics, STAT3 Transcription Factor metabolism, Signal Transduction, Suppressor of Cytokine Signaling 3 Protein, TOR Serine-Threonine Kinases genetics, TOR Serine-Threonine Kinases metabolism, Tumor Necrosis Factor-alpha genetics, Tumor Necrosis Factor-alpha metabolism, Carcinoma, Lewis Lung prevention & control, Hypoxia pathology, Melanoma, Experimental prevention & control, Neovascularization, Pathologic prevention & control, Paraneoplastic Syndromes, Ocular prevention & control, Suppressor of Cytokine Signaling Proteins physiology
- Abstract
Inflammatory cytokines and growth factors drive angiogenesis independently; however, their integrated role in pathologic and physiologic angiogenesis is not fully understood. Suppressor of cytokine signaling-3 (SOCS3) is an inducible negative feedback regulator of inflammation and growth factor signaling. In the present study, we show that SOCS3 curbs pathologic angiogenesis. Using a Cre/Lox system, we deleted SOCS3 in vessels and studied developmental and pathologic angiogenesis in murine models of oxygen-induced retinopathy and cancer. Conditional loss of SOCS3 leads to increased pathologic neovascularization, resulting in pronounced retinopathy and increased tumor size. In contrast, physiologic vascularization is not regulated by SOCS3. In vitro, SOCS3 knockdown increases proliferation and sprouting of endothelial cells costimulated with IGF-1 and TNFα via reduced feedback inhibition of the STAT3 and mTOR pathways. These results identify SOCS3 as a pivotal endogenous feedback inhibitor of pathologic angiogenesis and a potential therapeutic target acting at the converging crossroads of growth factor- and cytokine-induced vessel growth.
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- 2012
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5. Omega-3 polyunsaturated fatty acids preserve retinal function in type 2 diabetic mice.
- Author
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Sapieha P, Chen J, Stahl A, Seaward MR, Favazza TL, Juan AM, Hatton CJ, Joyal JS, Krah NM, Dennison RJ, Tang J, Kern TS, Akula JD, and Smith LE
- Abstract
Objective: Diabetic retinopathy (DR) is associated with hyperglycemia-driven microvascular pathology and neuronal compromise in the retina. However, DR is also linked to dyslipidemia. As omega-3 (ω-3) polyunsaturated fatty acids (PUFAs) are protective in proliferative retinopathy, we investigated the capacity of ω-3PUFAs to preserve retinal function in a mouse model of type 2 diabetes mellitus (T2DM)., Design: Male leptin-receptor-deficient (db/db) mice were maintained for 22 weeks (4 weeks-26 weeks of life) on calorically and compositionally matched diets, except for 2% enrichment in either ω-3 or ω-6PUFAs. Visual function was assessed at 9, 14 and 26 weeks by electroretinography. Retinal capillary and neuronal integrity, as well as glucose challenge responses, were assessed on each diet., Results: The ω-3PUFA diet significantly preserved retinal function in the mouse model of T2DM to levels similar to those observed in nondiabetic control mice on normal chow. Conversely, retinal function gradually deteriorated in db/db mice on a ω-6PUFA-rich diet. There was also an enhanced ability of ω-3PUFA-fed mice to respond to glucose challenge. The protection of visual function appeared to be independent of cytoprotective or anti-inflammatory effects of ω-3PUFAs., Conclusion: This study identifies beneficial effects of dietary ω-3PUFAs on visual function in T2DM. The data are consistent with dyslipidemia negatively impacting retinal function. As ω-3PUFA lipid dietary interventions are readily available, safe and inexpensive, increasing ω-3PUFA intake in diabetic patients may slow the progression of vision loss in T2DM.
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- 2012
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6. Retinal expression of Wnt-pathway mediated genes in low-density lipoprotein receptor-related protein 5 (Lrp5) knockout mice.
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Chen J, Stahl A, Krah NM, Seaward MR, Joyal JS, Juan AM, Hatton CJ, Aderman CM, Dennison RJ, Willett KL, Sapieha P, and Smith LE
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- Adaptor Proteins, Signal Transducing genetics, Amino Acid Transport Systems, Neutral genetics, Animals, Carrier Proteins genetics, Disease Models, Animal, Dishevelled Proteins, Eye Proteins genetics, Frizzled Receptors genetics, Gene Expression Regulation, Developmental, Humans, Low Density Lipoprotein Receptor-Related Protein-5 deficiency, Membrane Proteins genetics, Mice, Mice, Knockout, Nerve Tissue Proteins genetics, Oligonucleotide Array Sequence Analysis, Phosphoproteins genetics, Proto-Oncogene Proteins genetics, Retina growth & development, Retinal Vessels growth & development, Retinal Vessels metabolism, Reverse Transcriptase Polymerase Chain Reaction, Vitreoretinopathy, Proliferative genetics, Wnt Proteins genetics, Gene Expression Profiling, Low Density Lipoprotein Receptor-Related Protein-5 genetics, Retina metabolism, Wnt Signaling Pathway genetics
- Abstract
Mutations in low-density lipoprotein receptor-related protein 5 (Lrp5) impair retinal angiogenesis in patients with familial exudative vitreoretinopathy (FEVR), a rare type of blinding vascular eye disease. The defective retinal vasculature phenotype in human FEVR patients is recapitulated in Lrp5 knockout (Lrp5(-/-)) mouse with delayed and incomplete development of retinal vessels. In this study we examined gene expression changes in the developing Lrp5(-/-) mouse retina to gain insight into the molecular mechanisms that underlie the pathology of FEVR in humans. Gene expression levels were assessed with an Illumina microarray on total RNA from Lrp5(-/-) and WT retinas isolated on postnatal day (P) 8. Regulated genes were confirmed using RT-qPCR analysis. Consistent with a role in vascular development, we identified expression changes in genes involved in cell-cell adhesion, blood vessel morphogenesis and membrane transport in Lrp5(-/-) retina compared to WT retina. In particular, tight junction protein claudin5 and amino acid transporter slc38a5 are both highly down-regulated in Lrp5(-/-) retina. Similarly, several Wnt ligands including Wnt7b show decreased expression levels. Plasmalemma vesicle associated protein (plvap), an endothelial permeability marker, in contrast, is up-regulated consistent with increased permeability in Lrp5(-/-) retinas. Together these data suggest that Lrp5 regulates multiple groups of genes that influence retinal angiogenesis and may contribute to the pathogenesis of FEVR.
- Published
- 2012
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7. Resveratrol inhibits pathologic retinal neovascularization in Vldlr(-/-) mice.
- Author
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Hua J, Guerin KI, Chen J, Michán S, Stahl A, Krah NM, Seaward MR, Dennison RJ, Juan AM, Hatton CJ, Sapieha P, Sinclair DA, and Smith LE
- Subjects
- Administration, Oral, Animals, Blotting, Western, Endothelium, Vascular drug effects, Endothelium, Vascular metabolism, Female, Fluorescent Antibody Technique, Indirect, Glial Fibrillary Acidic Protein, Male, Mice, Mice, Inbred C57BL, Mice, Knockout, Nerve Tissue Proteins genetics, Nerve Tissue Proteins metabolism, RNA, Messenger metabolism, Resveratrol, Retina drug effects, Retina metabolism, Retinal Neovascularization metabolism, Retinal Telangiectasis metabolism, Reverse Transcriptase Polymerase Chain Reaction, Vascular Endothelial Growth Factor A genetics, Vascular Endothelial Growth Factor A metabolism, Angiogenesis Inhibitors administration & dosage, Antioxidants administration & dosage, Disease Models, Animal, Receptors, LDL genetics, Retinal Neovascularization prevention & control, Retinal Telangiectasis prevention & control, Stilbenes administration & dosage
- Abstract
Purpose: Macular telangiectasia (MacTel) is a vision-threatening retinal disease with unknown pathogenesis and no approved treatment. Very low-density lipoprotein receptor mutant mice (Vldlr(-/-)) exhibit critical features of MacTel such as retinal neovascularization and photoreceptor degeneration. In this study, the authors evaluate the therapeutic potential of resveratrol, a plant polyphenol, in Vldlr(-/-) mice as a model for MacTel., Methods: Vldlr(-/-) and wild-type mice at postnatal day (P) 21 to P60 or P10 to P30 were treated orally with resveratrol. The number of neovascular lesions was evaluated on retinal flatmounts, and resveratrol effects on endothelial cells were assessed by Western blot for phosphorylated ERK1/2, aortic ring, and migration assays. Vegf and Gfap expression was evaluated in laser-capture microdissected retinal layers of angiogenic lesions and nonlesion areas from Vldlr(-/-) and wild-type retinas., Results: From P15 onward, Vldlr(-/-) retinas develop vascular lesions associated with the local upregulation of Vegf in photoreceptors and Gfap in the inner retina. Oral resveratrol reduces lesion formation when administered either before or after disease onset. The reduction of vascular lesions in resveratrol-treated Vldlr(-/-) mice is associated with the suppression of retinal Vegf transcription. Resveratrol also reduces endothelial ERK1/2 signaling as well as the migration and proliferation of endothelial cells. Furthermore, a trend toward increased rhodopsin mRNA in Vldlr(-/-) retinas is observed., Conclusions: Oral administration of resveratrol is protective against retinal neovascular lesions in Vldlr(-/-) mice by inhibiting Vegf expression and angiogenic activation of retinal endothelial cells. These results suggest that resveratrol might be a safe and effective intervention for treating patients with MacTel.
- Published
- 2011
- Full Text
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8. 5-Lipoxygenase metabolite 4-HDHA is a mediator of the antiangiogenic effect of ω-3 polyunsaturated fatty acids.
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Sapieha P, Stahl A, Chen J, Seaward MR, Willett KL, Krah NM, Dennison RJ, Connor KM, Aderman CM, Liclican E, Carughi A, Perelman D, Kanaoka Y, Sangiovanni JP, Gronert K, and Smith LE
- Subjects
- Animals, Arachidonate 5-Lipoxygenase genetics, Blotting, Western, Cell Proliferation drug effects, Cells, Cultured, Cyclooxygenase 2 metabolism, Fatty Acids, Omega-6 therapeutic use, Humans, Immunohistochemistry, Male, Mice, Oxygen toxicity, PPAR gamma metabolism, Retinal Diseases chemically induced, Retinal Diseases drug therapy, Retinal Diseases metabolism, Reverse Transcriptase Polymerase Chain Reaction, Angiogenesis Inhibitors therapeutic use, Arachidonate 5-Lipoxygenase metabolism, Docosahexaenoic Acids metabolism, Fatty Acids, Omega-3 therapeutic use
- Abstract
Lipid signaling is dysregulated in many diseases with vascular pathology, including cancer, diabetic retinopathy, retinopathy of prematurity, and age-related macular degeneration. We have previously demonstrated that diets enriched in ω-3 polyunsaturated fatty acids (PUFAs) effectively reduce pathological retinal neovascularization in a mouse model of oxygen-induced retinopathy, in part through metabolic products that suppress microglial-derived tumor necrosis factor-α. To better understand the protective effects of ω-3 PUFAs, we examined the relative importance of major lipid metabolic pathways and their products in contributing to this effect. ω-3 PUFA diets were fed to four lines of mice deficient in each key lipid-processing enzyme (cyclooxygenase 1 or 2, or lipoxygenase 5 or 12/15), retinopathy was induced by oxygen exposure; only loss of 5-lipoxygenase (5-LOX) abrogated the protection against retinopathy of dietary ω-3 PUFAs. This protective effect was due to 5-LOX oxidation of the ω-3 PUFA lipid docosahexaenoic acid to 4-hydroxy-docosahexaenoic acid (4-HDHA). 4-HDHA directly inhibited endothelial cell proliferation and sprouting angiogenesis via peroxisome proliferator-activated receptor γ (PPARγ), independent of 4-HDHA's anti-inflammatory effects. Our study suggests that ω-3 PUFAs may be profitably used as an alternative or supplement to current anti-vascular endothelial growth factor (VEGF) treatment for proliferative retinopathy and points to the therapeutic potential of ω-3 PUFAs and metabolites in other diseases of vasoproliferation. It also suggests that cyclooxygenase inhibitors such as aspirin and ibuprofen (but not lipoxygenase inhibitors such as zileuton) might be used without losing the beneficial effect of dietary ω-3 PUFA.
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- 2011
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9. Postnatal weight gain modifies severity and functional outcome of oxygen-induced proliferative retinopathy.
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Stahl A, Chen J, Sapieha P, Seaward MR, Krah NM, Dennison RJ, Favazza T, Bucher F, Löfqvist C, Ong H, Hellström A, Chemtob S, Akula JD, and Smith LE
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- Age Factors, Animals, Animals, Newborn, Disease Models, Animal, Humans, Infant, Newborn, Mice, Mice, Inbred C57BL, Oxygen Inhalation Therapy adverse effects, Parturition physiology, Prognosis, Retina metabolism, Retinopathy of Prematurity genetics, Retinopathy of Prematurity pathology, Vascular Endothelial Growth Factor A genetics, Vascular Endothelial Growth Factor A metabolism, Oxygen adverse effects, Retinopathy of Prematurity diagnosis, Retinopathy of Prematurity etiology, Severity of Illness Index, Weight Gain physiology
- Abstract
In clinical studies, postnatal weight gain is strongly associated with retinopathy of prematurity (ROP). However, animal studies are needed to investigate the pathophysiological mechanisms of how postnatal weight gain affects the severity of ROP. In the present study, we identify nutritional supply as one potent parameter that affects the extent of retinopathy in mice with identical birth weights and the same genetic background. Wild-type pups with poor postnatal nutrition and poor weight gain (PWG) exhibit a remarkably prolonged phase of retinopathy compared to medium weight gain or extensive weight gain pups. A high (r(2) = 0.83) parabolic association between postnatal weight gain and oxygen-induced retinopathy severity is observed, as is a significantly prolonged phase of proliferative retinopathy in PWG pups (20 days) compared with extensive weight gain pups (6 days). The extended retinopathy is concomitant with prolonged overexpression of retinal vascular endothelial growth factor in PWG pups. Importantly, PWG pups show low serum levels of nonfasting glucose, insulin, and insulin-like growth factor-1 as well as high levels of ghrelin in the early postoxygen-induced retinopathy phase, a combination indicative of poor metabolic supply. These differences translate into visual deficits in adult PWG mice, as demonstrated by impaired bipolar and proximal neuronal function. Together, these results provide evidence for a pathophysiological correlation between poor postnatal nutritional supply, slow weight gain, prolonged retinal vascular endothelial growth factor overexpression, protracted retinopathy, and reduced final visual outcome.
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- 2010
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10. Short communication: PPAR gamma mediates a direct antiangiogenic effect of omega 3-PUFAs in proliferative retinopathy.
- Author
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Stahl A, Sapieha P, Connor KM, Sangiovanni JP, Chen J, Aderman CM, Willett KL, Krah NM, Dennison RJ, Seaward MR, Guerin KI, Hua J, and Smith LE
- Subjects
- Angiogenesis Inhibitors administration & dosage, Animals, Animals, Newborn, Cell Proliferation drug effects, Disease Models, Animal, Female, Mice, Mice, Inbred C57BL, Neovascularization, Pathologic diet therapy, Neovascularization, Pathologic prevention & control, Retinal Diseases diet therapy, Retinal Diseases prevention & control, Vascular Endothelial Growth Factor A physiology, Angiogenesis Inhibitors physiology, Fatty Acids, Omega-3 administration & dosage, Neovascularization, Pathologic metabolism, PPAR gamma physiology, Retinal Diseases metabolism
- Abstract
Rationale: Omega3 long-chain polyunsaturated fatty acids (omega3-PUFAs) are powerful modulators of angiogenesis. However, little is known about the mechanisms governing omega3-PUFA-dependent attenuation of angiogenesis., Objective: This study aims to identify a major mechanism by which omega3-PUFAs attenuate retinal neovascularization., Methods and Results: Administering omega3-PUFAs exclusively during the neovascular stage of the mouse model of oxygen-induced retinopathy induces a direct neovascularization reduction of more than 40% without altering vasoobliteration or the regrowth of normal vessels. Cotreatment with an inhibitor of peroxisome proliferator-activated receptor (PPAR)gamma almost completely abrogates this effect. Inhibition of PPARgamma also reverses the omega3-PUFA-induced reduction of retinal tumor necrosis factor-alpha, intercellular adhesion molecule-1, vascular cell adhesion molecule-1, endothelial selectin, and angiopoietin 2 but not vascular endothelial growth factor., Conclusions: These results identify a direct, PPARgamma-mediated effect of omega3-PUFAs on retinal neovascularization formation and retinal angiogenic activation that is independent of vascular endothelial growth factor.
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- 2010
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11. The mouse retina as an angiogenesis model.
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Stahl A, Connor KM, Sapieha P, Chen J, Dennison RJ, Krah NM, Seaward MR, Willett KL, Aderman CM, Guerin KI, Hua J, Löfqvist C, Hellström A, and Smith LE
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- Animals, Mice, Disease Models, Animal, Neovascularization, Physiologic physiology, Retinal Neovascularization physiopathology, Retinal Vessels physiology
- Abstract
The mouse retina has been used extensively over the past decades to study both physiologic and pathologic angiogenesis. Over time, various mouse retina models have evolved into well-characterized and robust tools for in vivo angiogenesis research. This article is a review of the angiogenic development of the mouse retina and a discussion of some of the most widely used vascular disease models. From the multitude of studies performed in the mouse retina, a selection of representative works is discussed in more detail regarding their role in advancing the understanding of both the ocular and general mechanisms of angiogenesis.
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- 2010
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12. Quantification of oxygen-induced retinopathy in the mouse: a model of vessel loss, vessel regrowth and pathological angiogenesis.
- Author
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Connor KM, Krah NM, Dennison RJ, Aderman CM, Chen J, Guerin KI, Sapieha P, Stahl A, Willett KL, and Smith LE
- Subjects
- Animals, Dissection, Oxygen, Regeneration, Retina pathology, Retinal Diseases pathology, Retinal Diseases physiopathology, Retinal Vessels growth & development, Retinal Vessels pathology, Disease Models, Animal, Mice, Neovascularization, Pathologic chemically induced, Retinal Diseases chemically induced, Retinal Vessels physiology
- Abstract
The mouse model of oxygen-induced retinopathy (OIR) has been widely used in studies related to retinopathy of prematurity, proliferative diabetic retinopathy and in studies evaluating the efficacy of antiangiogenic compounds. In this model, 7-d-old (P7) mouse pups with nursing mothers are subjected to hyperoxia (75% oxygen) for 5 d, which inhibits retinal vessel growth and causes significant vessel loss. On P12, mice are returned to room air and the hypoxic avascular retina triggers both normal vessel regrowth and retinal neovascularization (NV), which is maximal at P17. Neovascularization spontaneously regresses between P17 and P25. Although the OIR model has been the cornerstone of studies investigating proliferative retinopathies, there is currently no harmonized protocol to assess aspects of angiogenesis and treatment outcome. In this protocol we describe standards for mouse size, sample size, retinal preparation, quantification of vascular loss, vascular regrowth, NV and neovascular regression.
- Published
- 2009
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13. Computer-aided quantification of retinal neovascularization.
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Stahl A, Connor KM, Sapieha P, Willett KL, Krah NM, Dennison RJ, Chen J, Guerin KI, and Smith LE
- Subjects
- Algorithms, Animals, Animals, Newborn, Disease Models, Animal, Efficiency, Fluorescence, Mice, Neovascularization, Pathologic diagnostic imaging, Observer Variation, Oxygen, Retinal Neovascularization chemically induced, Retinal Neovascularization pathology, Radiographic Image Interpretation, Computer-Assisted methods, Retinal Neovascularization diagnostic imaging
- Abstract
Rodent models of retinal angiogenesis play a pivotal role in angiogenesis research. These models are a window to developmental angiogenesis, to pathological retinopathy, and are also in vivo tools for anti-angiogenic drug screening in cancer and ophthalmic research. The mouse model of oxygen-induced retinopathy (OIR) has emerged as one of the leading in vivo models for these purposes. Many of the animal studies that laid the foundation for the recent breakthrough of anti-angiogenic treatments into clinical practice were performed in the OIR model. However, readouts from the OIR model have been time-consuming and can vary depending on user experience. Here, we present a computer-aided quantification method that is characterized by (i) significantly improved efficiency, (ii) high correlation with the established hand-measurement protocols, and (iii) high intra- and inter-individual reproducibility of results. This method greatly facilitates quantification of retinal angiogenesis while at the same time increasing lab-to-lab reproducibility of one of the most widely used in vivo models in angiogenesis research.
- Published
- 2009
- Full Text
- View/download PDF
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