VEGF/Ang-2 imbalance: the crosslinking between methylglyoxal and vascular dysfunction in diabetic retinopathy

Detalhes bibliográficos
Autor(a) principal: Bento, C.
Data de Publicação: 2008
Outros Autores: Fernandes, R., Pereira, P.
Tipo de documento: Artigo
Idioma: eng
Título da fonte: Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos)
Texto Completo: http://hdl.handle.net/10316/8393
https://doi.org/10.1111/j.1755-3768.2008.611.x
Resumo: Purpose Accumulation of methylglyoxal (MGO) in retinas of diabetic rats has been implicated in the formation of acellular capillaries, suggesting an important role for MGO in the vascular dysfunction observed in diabetes. In this study, we hypothesize that increased levels of MGO in retinal pigment epithelium (RPE) cells disturbs the balance VEGF/Ang2 secreted to the extracellular milieu, promoting apoptotis and low proliferation of endothelial cells. Methods ARPE19 cells were subjected both to hypoxia and MGO, two main features of diabetic retinopathy (DR). The levels of VEGF and Ang2 secreted into the culture medium were assessed by ELISA. Retinal endothelial cells were subsequently treated with the pre-conditioned media of the ARPE19 cells, as well as with different ratios of VEGF and Ang2 recombinant proteins. Apoptotic cell death was determined by immunoblot against Bax and Bcl2, while endothelial cell proliferation was assessed by BrdU-incorporation and fibrin gel angiogenic assays. Results MGO increases the levels of Ang2 and strongly decreases the levels of VEGF secreted by ARPE19 cells in response to hypoxia. VEGF downregulation appears to result from increased degradation of HIF103B1 and low HIF1 transcriptional activity. The VEGF/Ang2 imbalance generated by MGO significantly increases the expression of BAX and decreases the levels of Bcl2 of endothelial cells. Moreover, this imbalance also leads to decreased proliferation of the endothelial cells. Conclusion The VEGF/Ang2 imbalance induced by MGO activates the apoptotic cascade and induces low proliferation of retinal endothelial cells, possibly leading to vessels regression in pathologies that favour accumulation of MGO and where hypoxia is also present, such as DR.
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spelling VEGF/Ang-2 imbalance: the crosslinking between methylglyoxal and vascular dysfunction in diabetic retinopathyPurpose Accumulation of methylglyoxal (MGO) in retinas of diabetic rats has been implicated in the formation of acellular capillaries, suggesting an important role for MGO in the vascular dysfunction observed in diabetes. In this study, we hypothesize that increased levels of MGO in retinal pigment epithelium (RPE) cells disturbs the balance VEGF/Ang2 secreted to the extracellular milieu, promoting apoptotis and low proliferation of endothelial cells. Methods ARPE19 cells were subjected both to hypoxia and MGO, two main features of diabetic retinopathy (DR). The levels of VEGF and Ang2 secreted into the culture medium were assessed by ELISA. Retinal endothelial cells were subsequently treated with the pre-conditioned media of the ARPE19 cells, as well as with different ratios of VEGF and Ang2 recombinant proteins. Apoptotic cell death was determined by immunoblot against Bax and Bcl2, while endothelial cell proliferation was assessed by BrdU-incorporation and fibrin gel angiogenic assays. Results MGO increases the levels of Ang2 and strongly decreases the levels of VEGF secreted by ARPE19 cells in response to hypoxia. VEGF downregulation appears to result from increased degradation of HIF103B1 and low HIF1 transcriptional activity. The VEGF/Ang2 imbalance generated by MGO significantly increases the expression of BAX and decreases the levels of Bcl2 of endothelial cells. Moreover, this imbalance also leads to decreased proliferation of the endothelial cells. Conclusion The VEGF/Ang2 imbalance induced by MGO activates the apoptotic cascade and induces low proliferation of retinal endothelial cells, possibly leading to vessels regression in pathologies that favour accumulation of MGO and where hypoxia is also present, such as DR.2008info:eu-repo/semantics/publishedVersioninfo:eu-repo/semantics/articlehttp://hdl.handle.net/10316/8393http://hdl.handle.net/10316/8393https://doi.org/10.1111/j.1755-3768.2008.611.xengActa Ophthalmologica. 86:s243 (2008) 0-0Bento, C.Fernandes, R.Pereira, P.info:eu-repo/semantics/openAccessreponame:Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos)instname:Agência para a Sociedade do Conhecimento (UMIC) - FCT - Sociedade da Informaçãoinstacron:RCAAP2020-05-25T02:23:14Zoai:estudogeral.uc.pt:10316/8393Portal AgregadorONGhttps://www.rcaap.pt/oai/openaireopendoar:71602024-03-19T20:43:33.589225Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos) - Agência para a Sociedade do Conhecimento (UMIC) - FCT - Sociedade da Informaçãofalse
dc.title.none.fl_str_mv VEGF/Ang-2 imbalance: the crosslinking between methylglyoxal and vascular dysfunction in diabetic retinopathy
title VEGF/Ang-2 imbalance: the crosslinking between methylglyoxal and vascular dysfunction in diabetic retinopathy
spellingShingle VEGF/Ang-2 imbalance: the crosslinking between methylglyoxal and vascular dysfunction in diabetic retinopathy
Bento, C.
title_short VEGF/Ang-2 imbalance: the crosslinking between methylglyoxal and vascular dysfunction in diabetic retinopathy
title_full VEGF/Ang-2 imbalance: the crosslinking between methylglyoxal and vascular dysfunction in diabetic retinopathy
title_fullStr VEGF/Ang-2 imbalance: the crosslinking between methylglyoxal and vascular dysfunction in diabetic retinopathy
title_full_unstemmed VEGF/Ang-2 imbalance: the crosslinking between methylglyoxal and vascular dysfunction in diabetic retinopathy
title_sort VEGF/Ang-2 imbalance: the crosslinking between methylglyoxal and vascular dysfunction in diabetic retinopathy
author Bento, C.
author_facet Bento, C.
Fernandes, R.
Pereira, P.
author_role author
author2 Fernandes, R.
Pereira, P.
author2_role author
author
dc.contributor.author.fl_str_mv Bento, C.
Fernandes, R.
Pereira, P.
description Purpose Accumulation of methylglyoxal (MGO) in retinas of diabetic rats has been implicated in the formation of acellular capillaries, suggesting an important role for MGO in the vascular dysfunction observed in diabetes. In this study, we hypothesize that increased levels of MGO in retinal pigment epithelium (RPE) cells disturbs the balance VEGF/Ang2 secreted to the extracellular milieu, promoting apoptotis and low proliferation of endothelial cells. Methods ARPE19 cells were subjected both to hypoxia and MGO, two main features of diabetic retinopathy (DR). The levels of VEGF and Ang2 secreted into the culture medium were assessed by ELISA. Retinal endothelial cells were subsequently treated with the pre-conditioned media of the ARPE19 cells, as well as with different ratios of VEGF and Ang2 recombinant proteins. Apoptotic cell death was determined by immunoblot against Bax and Bcl2, while endothelial cell proliferation was assessed by BrdU-incorporation and fibrin gel angiogenic assays. Results MGO increases the levels of Ang2 and strongly decreases the levels of VEGF secreted by ARPE19 cells in response to hypoxia. VEGF downregulation appears to result from increased degradation of HIF103B1 and low HIF1 transcriptional activity. The VEGF/Ang2 imbalance generated by MGO significantly increases the expression of BAX and decreases the levels of Bcl2 of endothelial cells. Moreover, this imbalance also leads to decreased proliferation of the endothelial cells. Conclusion The VEGF/Ang2 imbalance induced by MGO activates the apoptotic cascade and induces low proliferation of retinal endothelial cells, possibly leading to vessels regression in pathologies that favour accumulation of MGO and where hypoxia is also present, such as DR.
publishDate 2008
dc.date.none.fl_str_mv 2008
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dc.identifier.uri.fl_str_mv http://hdl.handle.net/10316/8393
http://hdl.handle.net/10316/8393
https://doi.org/10.1111/j.1755-3768.2008.611.x
url http://hdl.handle.net/10316/8393
https://doi.org/10.1111/j.1755-3768.2008.611.x
dc.language.iso.fl_str_mv eng
language eng
dc.relation.none.fl_str_mv Acta Ophthalmologica. 86:s243 (2008) 0-0
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