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PKCθ-JunB axis via upregulation of VEGFR3 expression mediates hypoxia-induced pathological retinal neovascularization

Pathological retinal neovascularization is the most common cause of vision loss. PKCθ has been shown to play a role in type 2 diabetes, which is linked to retinal neovascularization. Based on these clues, we have studied the role of PKCθ and its downstream target genes JunB and VEGFR3 in retinal neo...

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Autores principales: Kumar, Raj, Mani, Arul M., Singh, Nikhlesh K., Rao, Gadiparthi N.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7206019/
https://www.ncbi.nlm.nih.gov/pubmed/32382040
http://dx.doi.org/10.1038/s41419-020-2522-0
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author Kumar, Raj
Mani, Arul M.
Singh, Nikhlesh K.
Rao, Gadiparthi N.
author_facet Kumar, Raj
Mani, Arul M.
Singh, Nikhlesh K.
Rao, Gadiparthi N.
author_sort Kumar, Raj
collection PubMed
description Pathological retinal neovascularization is the most common cause of vision loss. PKCθ has been shown to play a role in type 2 diabetes, which is linked to retinal neovascularization. Based on these clues, we have studied the role of PKCθ and its downstream target genes JunB and VEGFR3 in retinal neovascularization using global and tissue-specific knockout mouse models along with molecular biological approaches. Here, we show that vascular endothelial growth factor A (VEGFA) induces PKCθ phosphorylation in human retinal microvascular endothelial cells (HRMVECs) and downregulation of its levels attenuates VEGFA-induced HRMVECs migration, sprouting and tube formation. Furthermore, the whole body deletion of PKCθ or EC-specific deletion of its target gene JunB inhibited hypoxia-induced retinal EC proliferation, tip cell formation and neovascularization. VEGFA also induced VEGFR3 expression via JunB downstream to PKCθ in the regulation of HRMVEC migration, sprouting, and tube formation in vitro and OIR-induced retinal EC proliferation, tip cell formation and neovascularization in vivo. In addition, VEGFA-induced VEGFR3 expression requires VEGFR2 activation upstream to PKCθ-JunB axis both in vitro and in vivo. Depletion of VEGFR2 or VEGFR3 levels attenuated VEGFA-induced HRMVEC migration, sprouting and tube formation in vitro and retinal neovascularization in vivo and it appears that these events were dependent on STAT3 activation. Furthermore, the observations using soluble VEGFR3 indicate that VEGFR3 mediates its effects on retinal neovascularization in a ligand dependent and independent manner downstream to VEGFR2. Together, these observations suggest that PKCθ-dependent JunB-mediated VEGFR3 expression targeting STAT3 activation is required for VEGFA/VEGFR2-induced retinal neovascularization.
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spelling pubmed-72060192020-05-13 PKCθ-JunB axis via upregulation of VEGFR3 expression mediates hypoxia-induced pathological retinal neovascularization Kumar, Raj Mani, Arul M. Singh, Nikhlesh K. Rao, Gadiparthi N. Cell Death Dis Article Pathological retinal neovascularization is the most common cause of vision loss. PKCθ has been shown to play a role in type 2 diabetes, which is linked to retinal neovascularization. Based on these clues, we have studied the role of PKCθ and its downstream target genes JunB and VEGFR3 in retinal neovascularization using global and tissue-specific knockout mouse models along with molecular biological approaches. Here, we show that vascular endothelial growth factor A (VEGFA) induces PKCθ phosphorylation in human retinal microvascular endothelial cells (HRMVECs) and downregulation of its levels attenuates VEGFA-induced HRMVECs migration, sprouting and tube formation. Furthermore, the whole body deletion of PKCθ or EC-specific deletion of its target gene JunB inhibited hypoxia-induced retinal EC proliferation, tip cell formation and neovascularization. VEGFA also induced VEGFR3 expression via JunB downstream to PKCθ in the regulation of HRMVEC migration, sprouting, and tube formation in vitro and OIR-induced retinal EC proliferation, tip cell formation and neovascularization in vivo. In addition, VEGFA-induced VEGFR3 expression requires VEGFR2 activation upstream to PKCθ-JunB axis both in vitro and in vivo. Depletion of VEGFR2 or VEGFR3 levels attenuated VEGFA-induced HRMVEC migration, sprouting and tube formation in vitro and retinal neovascularization in vivo and it appears that these events were dependent on STAT3 activation. Furthermore, the observations using soluble VEGFR3 indicate that VEGFR3 mediates its effects on retinal neovascularization in a ligand dependent and independent manner downstream to VEGFR2. Together, these observations suggest that PKCθ-dependent JunB-mediated VEGFR3 expression targeting STAT3 activation is required for VEGFA/VEGFR2-induced retinal neovascularization. Nature Publishing Group UK 2020-05-07 /pmc/articles/PMC7206019/ /pubmed/32382040 http://dx.doi.org/10.1038/s41419-020-2522-0 Text en © The Author(s) 2020 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
spellingShingle Article
Kumar, Raj
Mani, Arul M.
Singh, Nikhlesh K.
Rao, Gadiparthi N.
PKCθ-JunB axis via upregulation of VEGFR3 expression mediates hypoxia-induced pathological retinal neovascularization
title PKCθ-JunB axis via upregulation of VEGFR3 expression mediates hypoxia-induced pathological retinal neovascularization
title_full PKCθ-JunB axis via upregulation of VEGFR3 expression mediates hypoxia-induced pathological retinal neovascularization
title_fullStr PKCθ-JunB axis via upregulation of VEGFR3 expression mediates hypoxia-induced pathological retinal neovascularization
title_full_unstemmed PKCθ-JunB axis via upregulation of VEGFR3 expression mediates hypoxia-induced pathological retinal neovascularization
title_short PKCθ-JunB axis via upregulation of VEGFR3 expression mediates hypoxia-induced pathological retinal neovascularization
title_sort pkcθ-junb axis via upregulation of vegfr3 expression mediates hypoxia-induced pathological retinal neovascularization
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7206019/
https://www.ncbi.nlm.nih.gov/pubmed/32382040
http://dx.doi.org/10.1038/s41419-020-2522-0
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