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Journal ArticleDOI

Laser-induced choroidal neovascularization model to study age-related macular degeneration in mice.

TL;DR: This standardized protocol can be applied to transgenic mice and can include treatments with drugs, recombinant proteins, antibodies, adenoviruses and pre-microRNAs to aid in the search for new molecular regulators and the identification of novel targets for innovative treatments.
Abstract: The mouse model of laser-induced choroidal neovascularization (CNV) has been used extensively in studies of the exudative form of age-related macular degeneration (AMD). This experimental in vivo model relies on laser injury to perforate Bruch's membrane, resulting in subretinal blood vessel recruitment from the choroid. By recapitulating the main features of the exudative form of human AMD, this assay has served as the backbone for testing antiangiogenic therapies. This standardized protocol can be applied to transgenic mice and can include treatments with drugs, recombinant proteins, antibodies, adenoviruses and pre-microRNAs to aid in the search for new molecular regulators and the identification of novel targets for innovative treatments. This robust assay requires 7-14 d to complete, depending on the treatment applied and whether immunostaining is performed. This protocol includes details of how to induce CNV, including laser induction, lesion excision, processing and different approaches to quantify neoformed vasculature.
Citations
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Journal ArticleDOI
TL;DR: It is concluded that this resident immune cell of the retina cannot be simply regarded as bystander of disease but may instead be a potential therapeutic target to be modulated in the treatment of degenerative and inflammatory diseases ofThe retina.

402 citations

Journal ArticleDOI
Patrycja Nowak-Sliwinska1, Kari Alitalo2, Elizabeth Allen3, Andrey Anisimov2, Alfred C. Aplin4, Robert Auerbach5, Hellmut G. Augustin6, Hellmut G. Augustin7, David O. Bates8, Judy R. van Beijnum9, R. Hugh F. Bender10, Gabriele Bergers3, Gabriele Bergers11, Andreas Bikfalvi12, Joyce Bischoff13, Barbara C. Böck7, Barbara C. Böck6, Peter C. Brooks14, Federico Bussolino15, Bertan Cakir13, Peter Carmeliet3, Daniel Castranova16, Anca Maria Cimpean, Ondine Cleaver17, George Coukos18, George E. Davis19, Michele De Palma20, Anna Dimberg21, Ruud P.M. Dings22, Valentin Djonov23, Andrew C. Dudley24, Neil Dufton25, Sarah-Maria Fendt3, Napoleone Ferrara26, Marcus Fruttiger27, Dai Fukumura13, Bart Ghesquière3, Bart Ghesquière28, Yan Gong13, Robert J. Griffin22, Adrian L. Harris29, Christopher C.W. Hughes10, Nan W. Hultgren10, M. Luisa Iruela-Arispe30, Melita Irving18, Rakesh K. Jain13, Raghu Kalluri31, Joanna Kalucka3, Robert S. Kerbel32, Jan Kitajewski33, Ingeborg Klaassen34, Hynda K. Kleinmann35, Pieter Koolwijk18, Elisabeth Kuczynski32, Brenda R. Kwak1, Koen Marien, Juan M. Melero-Martin13, Lance L. Munn13, Roberto F. Nicosia4, Agnès Noël36, Jussi Nurro37, Anna-Karin Olsson21, Tatiana V. Petrova38, Kristian Pietras, Roberto Pili39, Jeffrey W. Pollard40, Mark J. Post41, Paul H.A. Quax42, Gabriel A. Rabinovich43, Marius Raica, Anna M. Randi25, Domenico Ribatti44, Curzio Rüegg45, Reinier O. Schlingemann18, Reinier O. Schlingemann34, Stefan Schulte-Merker, Lois E.H. Smith13, Jonathan W. Song46, Steven A. Stacker47, Jimmy Stalin, Amber N. Stratman16, Maureen Van de Velde36, Victor W.M. van Hinsbergh18, Peter B. Vermeulen48, Johannes Waltenberger49, Brant M. Weinstein16, Hong Xin26, Bahar Yetkin-Arik34, Seppo Ylä-Herttuala37, Mervin C. Yoder39, Arjan W. Griffioen9 
University of Geneva1, University of Helsinki2, Katholieke Universiteit Leuven3, University of Washington4, University of Wisconsin-Madison5, Heidelberg University6, German Cancer Research Center7, University of Nottingham8, VU University Amsterdam9, University of California, Irvine10, University of California, San Francisco11, French Institute of Health and Medical Research12, Harvard University13, Maine Medical Center14, University of Turin15, National Institutes of Health16, University of Texas Southwestern Medical Center17, University of Lausanne18, University of Missouri19, École Polytechnique Fédérale de Lausanne20, Uppsala University21, University of Arkansas for Medical Sciences22, University of Bern23, University of Virginia24, Imperial College London25, University of California, San Diego26, University College London27, Flanders Institute for Biotechnology28, University of Oxford29, University of California, Los Angeles30, University of Texas MD Anderson Cancer Center31, University of Toronto32, University of Illinois at Chicago33, University of Amsterdam34, George Washington University35, University of Liège36, University of Eastern Finland37, Ludwig Institute for Cancer Research38, Indiana University39, University of Edinburgh40, Maastricht University41, Loyola University Medical Center42, National Scientific and Technical Research Council43, University of Bari44, University of Fribourg45, Ohio State University46, University of Melbourne47, University of Antwerp48, University of Münster49
TL;DR: In vivo, ex vivo, and in vitro bioassays that are available for the evaluation of angiogenesis are described and critical aspects that are relevant for their execution and proper interpretation are highlighted.
Abstract: The formation of new blood vessels, or angiogenesis, is a complex process that plays important roles in growth and development, tissue and organ regeneration, as well as numerous pathological conditions. Angiogenesis undergoes multiple discrete steps that can be individually evaluated and quantified by a large number of bioassays. These independent assessments hold advantages but also have limitations. This article describes in vivo, ex vivo, and in vitro bioassays that are available for the evaluation of angiogenesis and highlights critical aspects that are relevant for their execution and proper interpretation. As such, this collaborative work is the first edition of consensus guidelines on angiogenesis bioassays to serve for current and future reference.

397 citations

Journal ArticleDOI
TL;DR: Results show that YAP/TAZ plays multifaceted roles for EC behaviors, proliferation, junction assembly, and metabolism in sprouting angiogenesis and barrier formation and maturation and could be a potential therapeutic target for treating neovascular diseases.
Abstract: Angiogenesis is a multistep process that requires coordinated migration, proliferation, and junction formation of vascular endothelial cells (ECs) to form new vessel branches in response to growth stimuli. Major intracellular signaling pathways that regulate angiogenesis have been well elucidated, but key transcriptional regulators that mediate these signaling pathways and control EC behaviors are only beginning to be understood. Here, we show that YAP/TAZ, a transcriptional coactivator that acts as an end effector of Hippo signaling, is critical for sprouting angiogenesis and vascular barrier formation and maturation. In mice, endothelial-specific deletion of Yap/Taz led to blunted-end, aneurysm-like tip ECs with fewer and dysmorphic filopodia at the vascular front, a hyper-pruned vascular network, reduced and disarranged distributions of tight and adherens junction proteins, disrupted barrier integrity, subsequent hemorrhage in growing retina and brain vessels, and reduced pathological choroidal neovascularization. Mechanistically, YAP/TAZ activates actin cytoskeleton remodeling, an important component of filopodia formation and junction assembly. Moreover, YAP/TAZ coordinates EC proliferation and metabolic activity by upregulating MYC signaling. Overall, these results show that YAP/TAZ plays multifaceted roles for EC behaviors, proliferation, junction assembly, and metabolism in sprouting angiogenesis and barrier formation and maturation and could be a potential therapeutic target for treating neovascular diseases.

255 citations


Cites methods from "Laser-induced choroidal neovascular..."

  • ...male mice according to a previously described method (72) with some...

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Journal ArticleDOI
TL;DR: This review provides an overview of recent studies that depict microglial responses in diverse retinal pathologies that have degeneration and chronic immune reactions as key pathophysiological components and discusses innovative immunomodulatory therapy strategies that dampen the detrimental immunological responses to improve disease outcome.
Abstract: The retina is a complex tissue with multiple cell layers that are highly ordered. Its sophisticated structure makes it especially sensitive to external or internal perturbations that exceed the homeostatic range. This necessitates the continuous surveillance of the retina for the detection of noxious stimuli. This task is mainly performed by microglia cells, the resident tissue macrophages which confer neuroprotection against transient pathophysiological insults. However, under sustained pathological stimuli, microglial inflammatory responses become dysregulated, often worsening disease pathology. In this review, we provide an overview of recent studies that depict microglial responses in diverse retinal pathologies that have degeneration and chronic immune reactions as key pathophysiological components. We also discuss innovative immunomodulatory therapy strategies that dampen the detrimental immunological responses to improve disease outcome.

189 citations


Cites background or methods from "Laser-induced choroidal neovascular..."

  • ...Briefly, laser photocoagulation results in the rupture of Bruch’s membrane, leading to the ingrowth of immature leaky blood vessels into the outer avascular retina (103)....

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  • ...We used the laser-induced choroidal neovascularization (CNV) mouse model that mimics features of exudative AMD to test this hypothesis (103)....

    [...]

  • ...Briefly, laser photocoagulation results in the rupture of the Bruch’s membrane, leading to the ingrowth of immature leaky blood vessels from the choroid to the subretinal space (103)....

    [...]

Journal ArticleDOI
TL;DR: An overview of the roles of microglia-mediated neuroinflammation in major retinal degenerative diseases like glaucoma, age-related macular degeneration, and diabetic retinopathy is given.
Abstract: Retinal degenerative diseases are major causes of vision loss and blindness worldwide and are characterized by chronic and progressive neuronal loss. One common feature of retinal degenerative diseases and brain neurodegenerative diseases is chronic neuroinflammation. There is growing evidence that retinal microglia, as in the brain, become activated in the course of retinal degenerative diseases, having a pivotal role in the initiation and propagation of the neurodegenerative process. A better understanding of the events elicited and mediated by retinal microglia will contribute to the clarification of disease etiology and might open new avenues for potential therapeutic interventions. This review aims at giving an overview of the roles of microglia-mediated neuroinflammation in major retinal degenerative diseases like glaucoma, age-related macular degeneration, and diabetic retinopathy.

171 citations


Cites background from "Laser-induced choroidal neovascular..."

  • ...In the laser photocoagulation animal model, known to induce choroidal neovascularization [147], the increased productions of intracellular adhesion molecule 1 (ICAM-1) and IL-6 were prevented by administration of astaxanthin, known by its antioxidative and anti-inflammatory properties [148], reinforcing the role of the inflammatory response in the disease....

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References
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Journal ArticleDOI
TL;DR: Estimates from data on low vision and blindness as defined in the International statistical classification of diseases, injuries and causes of death, 10th revision show cataract remains the leading cause of visual impairment in all regions of the world, except in the most developed countries.
Abstract: This paper presents estimates of the prevalence of visual impairment and its causes in 2002, based on the best available evidence derived from recent studies. Estimates were determined from data on low vision and blindness as defined in the International statistical classification of diseases, injuries and causes of death, 10th revision. The number of people with visual impairment worldwide in 2002 was in excess of 161 million, of whom about 37 million were blind. The burden of visual impairment is not distributed uniformly throughout the world: the least developed regions carry the largest share. Visual impairment is also unequally distributed across age groups, being largely confined to adults 50 years of age and older. A distribution imbalance is also found with regard to gender throughout the world: females have a significantly higher risk of having visual impairment than males. Notwithstanding the progress in surgical intervention that has been made in many countries over the last few decades, cataract remains the leading cause of visual impairment in all regions of the world, except in the most developed countries. Other major causes of visual impairment are, in order of importance, glaucoma, age-related macular degeneration, diabetic retinopathy and trachoma.

4,163 citations

Journal ArticleDOI
TL;DR: In this article, the prevalence and distribution of age-related macular degeneration (AMD) in the United States by age, race/ethnicity, and gender was estimated.
Abstract: Objective: To estimate the prevalence and distribution of age-related macular degeneration (AMD) in the United States by age, race/ethnicity, and gender.Methods: Summary prevalence estimates of drusen 125 pin or larger, neovascular AMD, and geographic atrophy were prepared separately for black and white persons in 5-year age intervals starting at 40 years. The estimated rates were based on a meta-analysis of recent population-based studies in the United States, Australia, and Europe. These rates were applied to 2000 US Census data and to projected US population figures for 2020 to estimate the number of the US population with drusen and AMD.Results: The overall prevalence of neovascular AMD and/or geographic atrophy in the US population 40 years and older is estimated to be 1.47% (95% confidence interval, 1.38%-1.55%), with 1.75 million citizens having AMD. The prevalence of AMD increased dramatically with age, with more than 15% of the white women older than 80 years having neovascular AMD and/or geographic atrophy. More than 7 million individuals had drusen measuring 125 pin or larger and were, therefore, at substantial risk of developing AMD. Owing to the rapidly aging population, the number of persons having AMD will increase by 50% to 2.95 million in 2020. Age-related macular degeneration was far more prevalent among white than among black persons.Conclusion: Age-related macular degeneration affects more than 1.75 million individuals in the United States. Owing to the rapid aging of the US population, this number will increase to almost 3 million by 2020.

2,389 citations

Journal ArticleDOI
TL;DR: It is demonstrated that aflibercept is an effective treatment for AMD, with the every-2-month regimen offering the potential to reduce the risk from monthly intravitreal injections and the burden of monthly monitoring.

1,894 citations

01 Jan 2004
TL;DR: Age-related macular degeneration was far more prevalent among white than among black persons, and the number of persons having AMD will increase by 50% to 2.95 million in 2020.
Abstract: To estimate the prevalence and distribution of age-related macular degeneration (AMD) in the United States by age, race/ethnicity, and gender. Summary prevalence estimates of drusen 125 microm or larger, neovascular AMD, and geographic atrophy were prepared separately for black and white persons in 5-year age intervals starting at 40 years. The estimated rates were based on a meta-analysis of recent population-based studies in the United States, Australia, and Europe. These rates were applied to 2000 US Census data and to projected US population figures for 2020 to estimate the number of the US population with drusen and AMD. The overall prevalence of neovascular AMD and/or geographic atrophy in the US population 40 years and older is estimated to be 1.47% (95% confidence interval, 1.38%-1.55%), with 1.75 million citizens having AMD. The prevalence of AMD increased dramatically with age, with more than 15% of the white women older than 80 years having neovascular AMD and/or geographic atrophy. More than 7 million individuals had drusen measuring 125 microm or larger and were, therefore, at substantial risk of developing AMD. Owing to the rapidly aging population, the number of persons having AMD will increase by 50% to 2.95 million in 2020. Age-related macular degeneration was far more prevalent among white than among black persons. Age-related macular degeneration affects more than 1.75 million individuals in the United States. Owing to the rapid aging of the US population, this number will increase to almost 3 million by 2020

1,850 citations

01 Jan 2009

725 citations