Nuclear factor kappa-B signaling is integral to ocular neovascularization in ischemia-independent microenvironment.

Retinal ischemia promotes the upregulation of VEGF expression and accounts for most pathological features of retinal neovascularization (NV). Paradoxically, VEGF remains the pivotal stimulator of ocular NV, despite the absence of ischemia. Therefore, the central question arises as to how the various...

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Autores principales:	Michael DeNiro, Futwan A Al-Mohanna
Formato:	article
Lenguaje:	EN
Publicado:	Public Library of Science (PLoS) 2014
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/25360f75bcd746709df611fc8d099b83
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spelling	oai:doaj.org-article:25360f75bcd746709df611fc8d099b832021-11-25T06:07:42ZNuclear factor kappa-B signaling is integral to ocular neovascularization in ischemia-independent microenvironment.1932-620310.1371/journal.pone.0101602https://doaj.org/article/25360f75bcd746709df611fc8d099b832014-01-01T00:00:00Zhttps://www.ncbi.nlm.nih.gov/pmc/articles/pmid/25050547/pdf/?tool=EBIhttps://doaj.org/toc/1932-6203Retinal ischemia promotes the upregulation of VEGF expression and accounts for most pathological features of retinal neovascularization (NV). Paradoxically, VEGF remains the pivotal stimulator of ocular NV, despite the absence of ischemia. Therefore, the central question arises as to how the various molecular mechanisms interplay in ischemia-independent NV. It's been suggested that NFκB plays a crucial role in the pathogenesis of diabetic vasculopathies. Here, we dissected the molecular mechanism of ocular NV in the rho/VEGF transgenic mouse model, which develops subretinal NV in ischemia-independent microenvironment. Furthermore, we examined whether intravitreal administration of YC-1, a HIF-1 inhibitor, can modulate the activation of NFκB and its downstream angiogenic signaling in the mouse retina. We demonstrated that YC-1 inhibited retinal NFκB/p65 DNA binding activity and downregulated NFκB/p65, FAK, α5β1, EPO, ET-1, and MMP-9 expression at the message and the protein levels. In addition, YC-1 significantly inhibited subretinal NV by reducing the number of neovascular lesions, the area of each lesion and the total area of NV per retina. We further investigated the influence of VEGF signaling pathway on HIF-1α transcriptional activity to substantiate that this mouse model develops subretinal NV in an ischemia-independent microenvironment. Our data demonstrated that VEGF overexpression didn't have any impact on HIF-1α transcriptional activity, whereas treatment with YC-1 significantly inhibited endogenous HIF-1 activity. Our study suggests that retinal NFκB transcriptional activity is pivotal to ischemia-independent mechanisms, which lead to the local activation of angiogenic cascades. Our data also indicate that the nexus between VEGF and NFκB is implicated in triggering the angiogenic cascade that promotes retinal NV. Hence, targeting the VEGF/NFκB axis may act in a negative feedback loop to suppress ocular NV. This study suggests that inhibition of NFκB activation may be a means of turning off a "master switch" responsible for initiating and perpetuating these ocular pathologies.Michael DeNiroFutwan A Al-MohannaPublic Library of Science (PLoS)articleMedicineRScienceQENPLoS ONE, Vol 9, Iss 7, p e101602 (2014)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Michael DeNiro Futwan A Al-Mohanna Nuclear factor kappa-B signaling is integral to ocular neovascularization in ischemia-independent microenvironment.
description	Retinal ischemia promotes the upregulation of VEGF expression and accounts for most pathological features of retinal neovascularization (NV). Paradoxically, VEGF remains the pivotal stimulator of ocular NV, despite the absence of ischemia. Therefore, the central question arises as to how the various molecular mechanisms interplay in ischemia-independent NV. It's been suggested that NFκB plays a crucial role in the pathogenesis of diabetic vasculopathies. Here, we dissected the molecular mechanism of ocular NV in the rho/VEGF transgenic mouse model, which develops subretinal NV in ischemia-independent microenvironment. Furthermore, we examined whether intravitreal administration of YC-1, a HIF-1 inhibitor, can modulate the activation of NFκB and its downstream angiogenic signaling in the mouse retina. We demonstrated that YC-1 inhibited retinal NFκB/p65 DNA binding activity and downregulated NFκB/p65, FAK, α5β1, EPO, ET-1, and MMP-9 expression at the message and the protein levels. In addition, YC-1 significantly inhibited subretinal NV by reducing the number of neovascular lesions, the area of each lesion and the total area of NV per retina. We further investigated the influence of VEGF signaling pathway on HIF-1α transcriptional activity to substantiate that this mouse model develops subretinal NV in an ischemia-independent microenvironment. Our data demonstrated that VEGF overexpression didn't have any impact on HIF-1α transcriptional activity, whereas treatment with YC-1 significantly inhibited endogenous HIF-1 activity. Our study suggests that retinal NFκB transcriptional activity is pivotal to ischemia-independent mechanisms, which lead to the local activation of angiogenic cascades. Our data also indicate that the nexus between VEGF and NFκB is implicated in triggering the angiogenic cascade that promotes retinal NV. Hence, targeting the VEGF/NFκB axis may act in a negative feedback loop to suppress ocular NV. This study suggests that inhibition of NFκB activation may be a means of turning off a "master switch" responsible for initiating and perpetuating these ocular pathologies.
format	article
author	Michael DeNiro Futwan A Al-Mohanna
author_facet	Michael DeNiro Futwan A Al-Mohanna
author_sort	Michael DeNiro
title	Nuclear factor kappa-B signaling is integral to ocular neovascularization in ischemia-independent microenvironment.
title_short	Nuclear factor kappa-B signaling is integral to ocular neovascularization in ischemia-independent microenvironment.
title_full	Nuclear factor kappa-B signaling is integral to ocular neovascularization in ischemia-independent microenvironment.
title_fullStr	Nuclear factor kappa-B signaling is integral to ocular neovascularization in ischemia-independent microenvironment.
title_full_unstemmed	Nuclear factor kappa-B signaling is integral to ocular neovascularization in ischemia-independent microenvironment.
title_sort	nuclear factor kappa-b signaling is integral to ocular neovascularization in ischemia-independent microenvironment.
publisher	Public Library of Science (PLoS)
publishDate	2014
url	https://doaj.org/article/25360f75bcd746709df611fc8d099b83
work_keys_str_mv	AT michaeldeniro nuclearfactorkappabsignalingisintegraltoocularneovascularizationinischemiaindependentmicroenvironment AT futwanaalmohanna nuclearfactorkappabsignalingisintegraltoocularneovascularizationinischemiaindependentmicroenvironment
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Nuclear factor kappa-B signaling is integral to ocular neovascularization in ischemia-independent microenvironment.

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