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      VEGFR1 signaling in retinal angiogenesis and microinflammation

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          Abstract

          Five vascular endothelial growth factor receptor (VEGFR) ligands (VEGF-A, -B, –C, -D, and placental growth factor [PlGF]) constitute the VEGF family. VEGF-A binds VEGF receptors 1 and 2 (VEGFR1/2), whereas VEGF-B and PlGF only bind VEGFR1. Although much research has been conducted on VEGFR2 to elucidate its key role in retinal diseases, recent efforts have shown the importance and involvement of VEGFR1 and its family of ligands in angiogenesis, vascular permeability, and microinflammatory cascades within the retina. Expression of VEGFR1 depends on the microenvironment, is differentially regulated under hypoxic and inflammatory conditions, and it has been detected in retinal and choroidal endothelial cells, pericytes, retinal and choroidal mononuclear phagocytes (including microglia), Müller cells, photoreceptor cells, and the retinal pigment epithelium. Whilst the VEGF-A decoy function of VEGFR1 is well established, consequences of its direct signaling are less clear. VEGFR1 activation can affect vascular permeability and induce macrophage and microglia production of proinflammatory and proangiogenic mediators. However the ability of the VEGFR1 ligands (VEGF-A, PlGF, and VEGF-B) to compete against each other for receptor binding and to heterodimerize complicates our understanding of the relative contribution of VEGFR1 signaling alone toward the pathologic processes seen in diabetic retinopathy, retinal vascular occlusions, retinopathy of prematurity, and age-related macular degeneration. Clinically, anti-VEGF drugs have proven transformational in these pathologies and their impact on modulation of VEGFR1 signaling is still an opportunity-rich field for further research.

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          Global Prevalence and Major Risk Factors of Diabetic Retinopathy

          OBJECTIVE To examine the global prevalence and major risk factors for diabetic retinopathy (DR) and vision-threatening diabetic retinopathy (VTDR) among people with diabetes. RESEARCH DESIGN AND METHODS A pooled analysis using individual participant data from population-based studies around the world was performed. A systematic literature review was conducted to identify all population-based studies in general populations or individuals with diabetes who had ascertained DR from retinal photographs. Studies provided data for DR end points, including any DR, proliferative DR, diabetic macular edema, and VTDR, and also major systemic risk factors. Pooled prevalence estimates were directly age-standardized to the 2010 World Diabetes Population aged 20–79 years. RESULTS A total of 35 studies (1980–2008) provided data from 22,896 individuals with diabetes. The overall prevalence was 34.6% (95% CI 34.5–34.8) for any DR, 6.96% (6.87–7.04) for proliferative DR, 6.81% (6.74–6.89) for diabetic macular edema, and 10.2% (10.1–10.3) for VTDR. All DR prevalence end points increased with diabetes duration, hemoglobin A1c, and blood pressure levels and were higher in people with type 1 compared with type 2 diabetes. CONCLUSIONS There are approximately 93 million people with DR, 17 million with proliferative DR, 21 million with diabetic macular edema, and 28 million with VTDR worldwide. Longer diabetes duration and poorer glycemic and blood pressure control are strongly associated with DR. These data highlight the substantial worldwide public health burden of DR and the importance of modifiable risk factors in its occurrence. This study is limited by data pooled from studies at different time points, with different methodologies and population characteristics.
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            Mechanisms and regulation of endothelial VEGF receptor signalling.

            Vascular endothelial growth factors (VEGFs) and their receptors (VEGFRs) are uniquely required to balance the formation of new blood vessels with the maintenance and remodelling of existing ones, during development and in adult tissues. Recent advances have greatly expanded our understanding of the tight and multi-level regulation of VEGFR2 signalling, which is the primary focus of this Review. Important insights have been gained into the regulatory roles of VEGFR-interacting proteins (such as neuropilins, proteoglycans, integrins and protein tyrosine phosphatases); the dynamics of VEGFR2 endocytosis, trafficking and signalling; and the crosstalk between VEGF-induced signalling and other endothelial signalling cascades. A clear understanding of this multifaceted signalling web is key to successful therapeutic suppression or stimulation of vascular growth.
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              The biology of VEGF and its receptors.

              Vascular endothelial growth factor (VEGF) is a key regulator of physiological angiogenesis during embryogenesis, skeletal growth and reproductive functions. VEGF has also been implicated in pathological angiogenesis associated with tumors, intraocular neovascular disorders and other conditions. The biological effects of VEGF are mediated by two receptor tyrosine kinases (RTKs), VEGFR-1 and VEGFR-2, which differ considerably in signaling properties. Non-signaling co-receptors also modulate VEGF RTK signaling. Currently, several VEGF inhibitors are undergoing clinical testing in several malignancies. VEGF inhibition is also being tested as a strategy for the prevention of angiogenesis, vascular leakage and visual loss in age-related macular degeneration.
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                Author and article information

                Journal
                9431859
                20937
                Prog Retin Eye Res
                Prog Retin Eye Res
                Progress in retinal and eye research
                1350-9462
                1873-1635
                5 June 2021
                25 February 2021
                September 2021
                19 September 2021
                : 84
                : 100954
                Affiliations
                [a ]Department of Retinal Vascular Biology, Nagoya City University Graduate School of Medical Sciences, 1 Kawasumi Mizuho-cho, Mizuho-ku, Nagoya, 467-8601, Japan
                [b ]UCL Institute of Ophthalmology, University College London, 11-43 Bath Street, London, EC1V 9EL, UK
                [c ]Schepens Eye Research Institute of Massachusetts Eye and Ear, 20 Staniford Street, Boston, MA, 02114, USA
                [d ]Angiogenesis Laboratory, Institute of Genetics and Biophysics “Adriano Buzzati-Traverso”, Via Pietro Castellino 111, 80131 Naples, Italy; ANBITION S.r.l., Via Manzoni 1, 80123, Naples, Italy
                [e ]Department of Ophthalmology, Charité–Universitätsmedizin Berlin, Hindenburgdamm 30, 12200 Berlin, and Augustenburger Platz 1, 13353, Berlin, Germany
                [f ]Sorbonne Université, INSERM, CNRS, Institut de la Vision, 17 rue Moreau, F-75012, Paris, France
                [g ]Bayer Consumer Care AG, Pharmaceuticals, Peter-Merian-Strasse 84, CH-4052 Basel, Switzerland
                [h ]Laboratory for Experimental Immunology of the Eye, Department of Ophthalmology, Faculty of Medicine and University Hospital Cologne, University of Cologne, Joseph-Stelzmann-Str. 9, 50931, Cologne, Germany
                Author notes

                Author contributions

                Percentage of work contributed by each author in the production of the manuscript is as follows: Akiyoshi Uemura 9%, Marcus Fruttiger 9%, Patricia A. D’Amore 9%, Sandro De Falco 9%, Antonia M. Joussen 9%, Florian Sennlaub 9%, Lynne R. Brunck 9%, Kristian T. Johnson 9%, George N. Lambrou 9%, Kay D. Rittenhouse 9%, Thomas Langmann 9%

                CRediT authorship contribution statement

                Akiyoshi Uemura: Conceptualization, Methodology, Validation, Formal analysis, Investigation, Resources, Writing – original draft, Writing – review & editing, Visualization, Project administration. Marcus Fruttiger: Conceptualization, Methodology, Validation, Formal analysis, Investigation, Writing – original draft, Writing – review & editing, Supervision, Project administration. Patricia A. D’Amore: Conceptualization, Methodology, Investigation, Writing – original draft, Writing – review & editing. Sandro De Falco: Conceptualization, Methodology, Validation, Formal analysis, Investigation, Resources, Writing – original draft, Writing – review & editing, Visualization, Project administration. Antonia M. Joussen: Conceptualization, Methodology, Validation, Formal analysis, Investigation, Resources, Data curation, Writing – original draft, Writing – review & editing, Visualization. Florian Sennlaub: Conceptualization, Writing – original draft, Writing – review & editing, Visualization. Lynne R. Brunck: Conceptualization, Methodology, Formal analysis, Investigation, Writing – original draft, Writing – review & editing, Visualization, Supervision, Project administration, Funding acquisition. Kristian T. Johnson: Conceptualization, Methodology, Formal analysis, Investigation, Writing – original draft, Writing – review & editing, Visualization, Supervision, Project administration, Funding acquisition. George N. Lambrou: Conceptualization, Methodology, Formal analysis, Investigation, Writing – original draft, Writing – review & editing, Visualization, Supervision, Project administration, Funding acquisition. Kay D. Rittenhouse: Conceptualization, Methodology, Formal analysis, Investigation, Writing – original draft, Writing – review & editing, Visualization, Supervision, Project administration, Funding acquisition. Thomas Langmann: Conceptualization, Methodology, Validation, Investigation, Resources, Writing – original draft, Writing – review & editing, Visualization, Supervision.

                [* ]Corresponding author. UCL Institute of Ophthalmology, University College London, 11-43, Bath Street, London, EC1V 9EL, UK. m.fruttiger@ 123456ucl.ac.uk (M. Fruttiger)
                Article
                NIHMS1711356
                10.1016/j.preteyeres.2021.100954
                8385046
                33640465
                de9696eb-571f-4c2a-b238-91cb798ae44e

                This is an open access article under the CC BY license ( http://creativecommons.org/licenses/by/4.0/).

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