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Betacellulin Induces Increased Retinal Vascular Permeability in Mice

BACKGROUND: Diabetic maculopathy, the leading cause of vision loss in patients with type 2 diabetes, is characterized by hyper-permeability of retinal blood vessels with subsequent formation of macular edema and hard exudates. The degree of hyperglycemia and duration of diabetes have been suggested...

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Autores principales: Anand-Apte, Bela, Ebrahem, Quteba, Cutler, Alecia, Farage, Eric, Sugimoto, Masahiko, Hollyfield, Joe, Folkman, Judah
Formato: Texto
Lenguaje:English
Publicado: Public Library of Science 2010
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2956654/
https://www.ncbi.nlm.nih.gov/pubmed/20976146
http://dx.doi.org/10.1371/journal.pone.0013444
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author Anand-Apte, Bela
Ebrahem, Quteba
Cutler, Alecia
Farage, Eric
Sugimoto, Masahiko
Hollyfield, Joe
Folkman, Judah
author_facet Anand-Apte, Bela
Ebrahem, Quteba
Cutler, Alecia
Farage, Eric
Sugimoto, Masahiko
Hollyfield, Joe
Folkman, Judah
author_sort Anand-Apte, Bela
collection PubMed
description BACKGROUND: Diabetic maculopathy, the leading cause of vision loss in patients with type 2 diabetes, is characterized by hyper-permeability of retinal blood vessels with subsequent formation of macular edema and hard exudates. The degree of hyperglycemia and duration of diabetes have been suggested to be good predictors of retinal complications. Intervention studies have determined that while intensive treatment of diabetes reduced the development of proliferative diabetic retinopathy it was associated with a two to three-fold increased risk of severe hypoglycemia. Thus we hypothesized the need to identify downstream glycemic targets, which induce retinal vascular permeability that could be targeted therapeutically without the additional risks associated with intensive treatment of the hyperglycemia. Betacellulin is a 32 kD member of the epidermal growth factor family with mitogenic properties for the retinal pigment epithelial cells. This led us to hypothesize a role for betacellulin in the retinal vascular complications associated with diabetes. METHODS AND FINDINGS: In this study, using a mouse model of diabetes, we demonstrate that diabetic mice have accentuated retinal vascular permeability with a concomitant increased expression of a cleaved soluble form of betacellulin (s-Btc) in the retina. Intravitreal injection of soluble betacellulin induced retinal vascular permeability in normoglycemic and hyperglycemic mice. Western blot analysis of retinas from patients with diabetic retinopathy showed an increase in the active soluble form of betacellulin. In addition, an increase in the levels of A disintegrin and metalloproteinase (ADAM)-10 which plays a role in the cleavage of betacellulin was seen in the retinas of diabetic mice and humans. CONCLUSIONS: These results suggest that excessive amounts of betacellulin in the retina may contribute to the pathogenesis of diabetic macular edema.
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spelling pubmed-29566542010-10-25 Betacellulin Induces Increased Retinal Vascular Permeability in Mice Anand-Apte, Bela Ebrahem, Quteba Cutler, Alecia Farage, Eric Sugimoto, Masahiko Hollyfield, Joe Folkman, Judah PLoS One Research Article BACKGROUND: Diabetic maculopathy, the leading cause of vision loss in patients with type 2 diabetes, is characterized by hyper-permeability of retinal blood vessels with subsequent formation of macular edema and hard exudates. The degree of hyperglycemia and duration of diabetes have been suggested to be good predictors of retinal complications. Intervention studies have determined that while intensive treatment of diabetes reduced the development of proliferative diabetic retinopathy it was associated with a two to three-fold increased risk of severe hypoglycemia. Thus we hypothesized the need to identify downstream glycemic targets, which induce retinal vascular permeability that could be targeted therapeutically without the additional risks associated with intensive treatment of the hyperglycemia. Betacellulin is a 32 kD member of the epidermal growth factor family with mitogenic properties for the retinal pigment epithelial cells. This led us to hypothesize a role for betacellulin in the retinal vascular complications associated with diabetes. METHODS AND FINDINGS: In this study, using a mouse model of diabetes, we demonstrate that diabetic mice have accentuated retinal vascular permeability with a concomitant increased expression of a cleaved soluble form of betacellulin (s-Btc) in the retina. Intravitreal injection of soluble betacellulin induced retinal vascular permeability in normoglycemic and hyperglycemic mice. Western blot analysis of retinas from patients with diabetic retinopathy showed an increase in the active soluble form of betacellulin. In addition, an increase in the levels of A disintegrin and metalloproteinase (ADAM)-10 which plays a role in the cleavage of betacellulin was seen in the retinas of diabetic mice and humans. CONCLUSIONS: These results suggest that excessive amounts of betacellulin in the retina may contribute to the pathogenesis of diabetic macular edema. Public Library of Science 2010-10-18 /pmc/articles/PMC2956654/ /pubmed/20976146 http://dx.doi.org/10.1371/journal.pone.0013444 Text en Anand-Apte et al. http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are properly credited.
spellingShingle Research Article
Anand-Apte, Bela
Ebrahem, Quteba
Cutler, Alecia
Farage, Eric
Sugimoto, Masahiko
Hollyfield, Joe
Folkman, Judah
Betacellulin Induces Increased Retinal Vascular Permeability in Mice
title Betacellulin Induces Increased Retinal Vascular Permeability in Mice
title_full Betacellulin Induces Increased Retinal Vascular Permeability in Mice
title_fullStr Betacellulin Induces Increased Retinal Vascular Permeability in Mice
title_full_unstemmed Betacellulin Induces Increased Retinal Vascular Permeability in Mice
title_short Betacellulin Induces Increased Retinal Vascular Permeability in Mice
title_sort betacellulin induces increased retinal vascular permeability in mice
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2956654/
https://www.ncbi.nlm.nih.gov/pubmed/20976146
http://dx.doi.org/10.1371/journal.pone.0013444
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