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      Aumento da imunorreatividade ao VEGFR-1 no complexo coroido-escleral em modelo experimental de hipercolesterolemia Translated title: Increased VEGFR-1 immunoreactivity in the choroid-scleral complex in hypercholesterolemia experimental model

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          Abstract

          OBJETIVO: O objetivo deste trabalho é investigar a expressão do fator de crescimento vascular endotelial (VEGF) na coroide e esclera, utilizando um modelo experimental de hipercolesterolemia. MÉTODO: Coelhos New Zealand foram organizados em dois grupos: O grupo dieta normal (GN), composto por 8 coelhos (8 olhos), recebeu ração padrão para coelhos, durante 4 semanas; e o grupo hipercolesterolêmico (GH), composto por 13 coelhos (13 olhos), recebeu dieta rica em colesterol a 1% por 8 semanas. Foi realizada a dosagem sérica de colesterol total, triglicerídeos, HDL colesterol, glicemia de jejum no início do experimento e no momento da eutanásia. Ao final da 8ª semana para o GH e 4ª semana para o GN foi realizada a eutanásia dos animais e os olhos foram submetidos à análise imuno-histoquímica com os anticorpos RAM-11 e VEGFR-1. RESULTADOS: Observou-se significativo aumento do colesterol total e triglicerídeos do GH em relação ao GN (p<0,001). Houve significativo aumento da expressão da RAM-11 e VEGFR-1 na coroide e esclera dos animais do GH em relação ao GN (p<0,001). CONCLUSÃO: Este estudo demonstra que a dieta hipercolesterolêmica em coelhos induz ao aumento da concentração de macrófagos e da imunorreatividade ao VEGFR-1 na coroide e esclera, expressando similaridade com a degeneração macular relacionada à idade (DMRI) humana.

          Translated abstract

          PURPOSE: The aim of this study is to investigate the expression of vascular endothelial growth factor (VEGF) in the choroid and sclera using hypercholesterolemia experimental model. METHODS: New Zealand rabbits were divided into two groups: 8 rabbits (8 eyes), in the normal diet group (NG), were fed by a standard diet for 4 weeks; and 13 rabbits (13 eyes), in the hypercholesterolemic group (HG), were fed by a 1% cholesterol-enriched diet for 8 weeks. Total serum cholesterol, triglyceride, HDL cholesterol and fasting blood glucose exams were performed at the initiation of the experiment and at the euthanasia time. After hypercholesterolemic group 8th week and NG 4th week, animals were euthanized and their eyes underwent immunohistochemical analysis with the RAM-11 and VEGFR-1). RESULTS: The diet has induced a significant increase in total cholesterol and triglyceride levels in HG when compared with NG (p<0.001). There was a significant increase in the RAM-11 and VEGFR-1 expressions in hypercholesterolemic group choroid and sclera in relation to NG (p<0,001). CONCLUSION: This study has revealed that the hypercholesterolemic diet in rabbits induces an increase in the macrophage concentration and immunoreactivity to VEGFR-1 in the choroid and sclera, resembling human age-related macular degeneration (ARMD).

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          Vascular-specific growth factors and blood vessel formation.

          A recent explosion in newly discovered vascular growth factors has coincided with exploitation of powerful new genetic approaches for studying vascular development. An emerging rule is that all of these factors must be used in perfect harmony to form functional vessels. These new findings also demand re-evaluation of therapeutic efforts aimed at regulating blood vessel growth in ischaemia, cancer and other pathological settings.
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            Morphometric analysis of Bruch's membrane, the choriocapillaris, and the choroid in aging.

            To quantify changes in choriocapillary density and in thickness of Bruch's membrane, the choriocapillaris, and the choroid in 95 unpaired, histologically normal human maculae aged 6 to 100 years and in 25 maculae with advanced age-related macular degeneration. Light microscopic, computer-aided, morphometric quantitative analysis. In ten decades, Bruch's membrane thickness increased by 135%, from 2.0 to 4.7 microns; the choriocapillary density decreased by 45%; the diameter of the choriocapillaris decreased by 34%, from 9.8 to 6.5 microns; and the choroidal thickness decreased by 57%, from 193.5 to 84 microns in normal maculae. In maculae with basal laminar deposit, geographic atrophy, or disciform scarring, the density of the choriocapillaris was 63%, 54%, and 43% of normal and the choriocapillary diameter was 81%, 73%, and 75% of normal, respectively. Choroidal thickness remained unchanged. Thickness of Bruch's membrane was only related to age (rs = 0.63) and not to age-related atrophy of the choriocapillaris. Age was also the strongest factor related to choriocapillary density (rs = -0.58). In advanced stages of age-related macular degeneration, the decrease in choriocapillary density and diameter was significantly larger than in normal maculae, but the thickness of the choroid and Bruch's membrane was the same. The latter was significantly thinner (81% of normal) in disciform scarring.
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              Prevention of experimental choroidal neovascularization with intravitreal anti-vascular endothelial growth factor antibody fragment.

              To evaluate the safety and efficacy of intravitreal injections of an antigen-binding fragment of a recombinant humanized monoclonal antibody directed toward vascular endothelial growth factor (rhuFab VEGF) in a monkey model of choroidal neovascularization (CNV). In phase 1 of the study, each animal received intravitreal injections, 500 microg per eye, of rhuFab VEGF in one eye (prevention eye), while the contralateral eye received rhuFab VEGF vehicle (control eye) at 2-week intervals. On day 21, laser photocoagulation was performed to induce CNV. In phase 2, the vehicle-treated eye was crossed over and both eyes received 500 microg of rhuFab VEGF beginning 21 days following laser-induced injury at days 42 and 56. The eyes were monitored by ophthalmic examinations, color photographs, and fluorescein angiography. rhuFab VEGF did not cause any ocular hemorrhages. All eyes treated with rhuFab VEGF developed acute anterior chamber inflammation within 24 hours of the first injection that resolved within 1 week, and this inflammation was less severe with subsequent injections. The incidence of CNV, defined angiographically, was significantly lower in the prevention eyes than the control eyes (P<.001). Subsequent treatments were associated with less leakage in eyes with established CNV that were crossed over from the control eyes to the treatment eyes (P =.001). Intravitreal rhuFab VEGF injections prevented formation of clinically significant CNV in cynomolgus monkeys and decreased leakage of already formed CNV with no significant toxic effects. This study provides the nonclinical proof of principle for ongoing clinical studies of intravitreally injected rhuFab VEGF in patients with neovascular age-related macular degeneration.
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                Author and article information

                Contributors
                Role: ND
                Role: ND
                Role: ND
                Role: ND
                Role: ND
                Role: ND
                Role: ND
                Role: ND
                Role: ND
                Journal
                abo
                Arquivos Brasileiros de Oftalmologia
                Arq. Bras. Oftalmol.
                Conselho Brasileiro de Oftalmologia (São Paulo, SP, Brazil )
                0004-2749
                1678-2925
                February 2013
                : 76
                : 1
                : 1-5
                Affiliations
                [08] Curitiba PR orgnamePontifícia Universidade Católica do Paraná - PUCPR orgdiv1Departamento de Cardiologia Brasil
                [06] Curitiba PR orgnameCentro Oftalmológico de Curitiba Brasil
                [02] Curitiba PR orgnamePontifícia Universidade Católica do Paraná - PUCPR orgdiv1Departamento de Patologia Brasil
                [07] Curitiba Paraná orgnamePontifícia Universidade Católica do Paraná - PUCPR orgdiv1Departamento de Cirurgia Brasil
                [05] Curitiba PR orgnamePontifícia Universidade Católica do Paraná - PUCPR orgdiv1Biotério Central Brasil
                [04] Curitiba PR orgnamePontifícia Universidade Católica do Paraná - PUCPR orgdiv1Acadêmica de Medicina Brasil
                [01] Curitiba PR orgnamePontifícia Universidade Católica do Paraná - PUCPR orgdiv1Departamento de Oftalmologia Brasil
                [03] Londrina PR orgnameUniversidade Estadual de Londrina - UEL orgdiv1Departamento de Oftalmologia Brasil
                Article
                S0004-27492013000100002
                10.1590/S0004-27492013000100002
                23812517
                3f7fceee-e3d7-4e0c-94aa-5436ea0a18c0

                This work is licensed under a Creative Commons Attribution 4.0 International License.

                History
                : 09 February 2012
                : 13 November 2012
                Page count
                Figures: 0, Tables: 0, Equations: 0, References: 30, Pages: 5
                Product

                SciELO Brazil


                Cholesterol,Coelhos,Animais,Esclera,Coroide,Colesterol,Macrófagos,Degeneração macular,Fator A de crescimento do endotélio vascular,Rabbits,Animals,Sclera,Choroid,Macrophages,Macular degeneration,Vascular endothelial growth factor A

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