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Neurofibromin Deficiency Induces Endothelial Cell Proliferation and Retinal Neovascularization

PURPOSE: Neurofibromatosis type 1 (NF1) is the result of inherited mutations in the NF1 tumor suppressor gene, which encodes the protein neurofibromin. Eye manifestations are common in NF1 with recent reports describing a vascular dysplasia in the retina and choroid. Common features of NF1 retinopat...

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Autores principales: Zhang, Hanfang, Hudson, Farlyn Z., Xu, Zhimin, Tritz, Rebekah, Rojas, Modesto, Patel, Chintan, Haigh, Stephen B., Bordán, Zsuzsanna, Ingram, David A., Fulton, David J., Weintraub, Neal L., Caldwell, Ruth B., Stansfield, Brian K.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: The Association for Research in Vision and Ophthalmology 2018
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5963003/
https://www.ncbi.nlm.nih.gov/pubmed/29847659
http://dx.doi.org/10.1167/iovs.17-22588
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author Zhang, Hanfang
Hudson, Farlyn Z.
Xu, Zhimin
Tritz, Rebekah
Rojas, Modesto
Patel, Chintan
Haigh, Stephen B.
Bordán, Zsuzsanna
Ingram, David A.
Fulton, David J.
Weintraub, Neal L.
Caldwell, Ruth B.
Stansfield, Brian K.
author_facet Zhang, Hanfang
Hudson, Farlyn Z.
Xu, Zhimin
Tritz, Rebekah
Rojas, Modesto
Patel, Chintan
Haigh, Stephen B.
Bordán, Zsuzsanna
Ingram, David A.
Fulton, David J.
Weintraub, Neal L.
Caldwell, Ruth B.
Stansfield, Brian K.
author_sort Zhang, Hanfang
collection PubMed
description PURPOSE: Neurofibromatosis type 1 (NF1) is the result of inherited mutations in the NF1 tumor suppressor gene, which encodes the protein neurofibromin. Eye manifestations are common in NF1 with recent reports describing a vascular dysplasia in the retina and choroid. Common features of NF1 retinopathy include tortuous and dilated feeder vessels that terminate in capillary tufts, increased endothelial permeability, and neovascularization. Given the retinal vascular phenotype observed in persons with NF1, we hypothesize that preserving neurofibromin may be a novel strategy to control pathologic retinal neovascularization. METHODS: Nf1 expression in human endothelial cells (EC) was reduced using small hairpin (sh) RNA and EC proliferation, migration, and capacity to form vessel-like networks were assessed in response to VEGF and hypoxia. Wild-type (WT), Nf1 heterozygous (Nf1(+/−)), and Nf1(flox/+);Tie2cre pups were subjected to hyperoxia/hypoxia using the oxygen-induced retinopathy model. Retinas were analyzed quantitatively for extent of retinal vessel dropout, neovascularization, and capillary branching. RESULTS: Neurofibromin expression was suppressed in response to VEGF, which corresponded with activation of Mek-Erk and PI3-K-Akt signaling. Neurofibromin-deficient EC exhibited enhanced proliferation and network formation in response to VEGF and hypoxia via an Akt-dependent mechanism. In response to hyperoxia/hypoxia, Nf1(+/−) retinas exhibited increased vessel dropout and neovascularization when compared with WT retinas. Neovascularization was similar between Nf1(+/−) and Nf1(flox/+);Tie2cre retinas, but capillary drop out in Nf1(flox/+);Tie2cre retinas was significantly reduced when compared with Nf1(+/−) retinas. CONCLUSIONS: These data suggest that neurofibromin expression is essential for controlling endothelial cell proliferation and retinal neovascularization and therapies targeting neurofibromin-deficient EC may be beneficial.
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spelling pubmed-59630032018-05-24 Neurofibromin Deficiency Induces Endothelial Cell Proliferation and Retinal Neovascularization Zhang, Hanfang Hudson, Farlyn Z. Xu, Zhimin Tritz, Rebekah Rojas, Modesto Patel, Chintan Haigh, Stephen B. Bordán, Zsuzsanna Ingram, David A. Fulton, David J. Weintraub, Neal L. Caldwell, Ruth B. Stansfield, Brian K. Invest Ophthalmol Vis Sci Retina PURPOSE: Neurofibromatosis type 1 (NF1) is the result of inherited mutations in the NF1 tumor suppressor gene, which encodes the protein neurofibromin. Eye manifestations are common in NF1 with recent reports describing a vascular dysplasia in the retina and choroid. Common features of NF1 retinopathy include tortuous and dilated feeder vessels that terminate in capillary tufts, increased endothelial permeability, and neovascularization. Given the retinal vascular phenotype observed in persons with NF1, we hypothesize that preserving neurofibromin may be a novel strategy to control pathologic retinal neovascularization. METHODS: Nf1 expression in human endothelial cells (EC) was reduced using small hairpin (sh) RNA and EC proliferation, migration, and capacity to form vessel-like networks were assessed in response to VEGF and hypoxia. Wild-type (WT), Nf1 heterozygous (Nf1(+/−)), and Nf1(flox/+);Tie2cre pups were subjected to hyperoxia/hypoxia using the oxygen-induced retinopathy model. Retinas were analyzed quantitatively for extent of retinal vessel dropout, neovascularization, and capillary branching. RESULTS: Neurofibromin expression was suppressed in response to VEGF, which corresponded with activation of Mek-Erk and PI3-K-Akt signaling. Neurofibromin-deficient EC exhibited enhanced proliferation and network formation in response to VEGF and hypoxia via an Akt-dependent mechanism. In response to hyperoxia/hypoxia, Nf1(+/−) retinas exhibited increased vessel dropout and neovascularization when compared with WT retinas. Neovascularization was similar between Nf1(+/−) and Nf1(flox/+);Tie2cre retinas, but capillary drop out in Nf1(flox/+);Tie2cre retinas was significantly reduced when compared with Nf1(+/−) retinas. CONCLUSIONS: These data suggest that neurofibromin expression is essential for controlling endothelial cell proliferation and retinal neovascularization and therapies targeting neurofibromin-deficient EC may be beneficial. The Association for Research in Vision and Ophthalmology 2018-05 /pmc/articles/PMC5963003/ /pubmed/29847659 http://dx.doi.org/10.1167/iovs.17-22588 Text en Copyright 2018 The Authors http://creativecommons.org/licenses/by-nc-nd/4.0/ This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License.
spellingShingle Retina
Zhang, Hanfang
Hudson, Farlyn Z.
Xu, Zhimin
Tritz, Rebekah
Rojas, Modesto
Patel, Chintan
Haigh, Stephen B.
Bordán, Zsuzsanna
Ingram, David A.
Fulton, David J.
Weintraub, Neal L.
Caldwell, Ruth B.
Stansfield, Brian K.
Neurofibromin Deficiency Induces Endothelial Cell Proliferation and Retinal Neovascularization
title Neurofibromin Deficiency Induces Endothelial Cell Proliferation and Retinal Neovascularization
title_full Neurofibromin Deficiency Induces Endothelial Cell Proliferation and Retinal Neovascularization
title_fullStr Neurofibromin Deficiency Induces Endothelial Cell Proliferation and Retinal Neovascularization
title_full_unstemmed Neurofibromin Deficiency Induces Endothelial Cell Proliferation and Retinal Neovascularization
title_short Neurofibromin Deficiency Induces Endothelial Cell Proliferation and Retinal Neovascularization
title_sort neurofibromin deficiency induces endothelial cell proliferation and retinal neovascularization
topic Retina
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5963003/
https://www.ncbi.nlm.nih.gov/pubmed/29847659
http://dx.doi.org/10.1167/iovs.17-22588
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