Targeted Knockdown of Overexpressed VEGFA or VEGF164 in Müller cells maintains retinal function by triggering different signaling mechanisms

Oxygen-induced retinopathy (OIR) upregulates Müller cell vascular endothelial growth factor A (VEGFA) that causes intravitreal neovascularization similar to severe retinopathy of prematurity (ROP). Safety concerns exist with anti-VEGF treatment for ROP. We evaluated long-term knockdown of Müller cel...

Full description

Saved in:
Bibliographic Details
Published in:Scientific reports Vol. 8; no. 1; pp. 2003 - 13
Main Authors: Becker, Silke, Wang, Haibo, Simmons, Aaron B., Suwanmanee, Thipparat, Stoddard, Gregory J., Kafri, Tal, Hartnett, M. Elizabeth
Format: Journal Article
Language:English
Published: London Nature Publishing Group UK 31.01.2018
Nature Publishing Group
Subjects:
13/106
13/51
14/19
38/77
38/89
42/41
692/308
692/617
Animals
Astrocytes - metabolism
Brain-derived neurotrophic factor
Brain-Derived Neurotrophic Factor - metabolism
Cells, Cultured
Electroretinograms
Erythropoietin
Erythropoietin - metabolism
Gene Knockdown Techniques
Gene Silencing
Glial Cell Line-Derived Neurotrophic Factor - metabolism
Humanities and Social Sciences
multidisciplinary
Nerve growth factor
Nerve Growth Factor - metabolism
Neuronal-glial interactions
Neuroprotection
Neurotrophin 3
Neurotrophin 3 - metabolism
Rats
Rats, Sprague-Dawley
Retina
Retina - metabolism
Retina - pathology
Retinopathy
Retinopathy of Prematurity - metabolism
Rodents
Science
Science (multidisciplinary)
Signal Transduction
Structure-function relationships
Vascular endothelial growth factor
Vascular Endothelial Growth Factor A - genetics
Vascular Endothelial Growth Factor A - metabolism
Vascularization
ISSN:2045-2322, 2045-2322
Online Access:Get full text
Tags: Add Tag
No Tags, Be the first to tag this record!
Description
Summary:Oxygen-induced retinopathy (OIR) upregulates Müller cell vascular endothelial growth factor A (VEGFA) that causes intravitreal neovascularization similar to severe retinopathy of prematurity (ROP). Safety concerns exist with anti-VEGF treatment for ROP. We evaluated long-term knockdown of Müller cell-VEGFA with short-hairpin RNAs to VEGFA or VEGF 164 via subretinal lentivirus delivery (L-VEGFAshRNA, L-VEGF164shRNA) on retinal structure and function in a rat OIR model. Lectin-stained retinal flat mounts analyzed for areas of avascular/total retina (AVA) and intravitreal neovascular/total retina (IVNV) showed initial significantly reduced IVNV by L-VEGFAshRNA and L-VEGF164shRNA compared to control, luciferase-shRNA lentivirus, without late recurrence. Spectral-domain optical coherence tomography (OCT) and immunohistochemical sections (IHC) demonstrated changes in retinal layer thicknesses in L-VEGFAshRNA or L-VEGF164shRNA  compared to control. Ganzfeld electroretinograms were increased in L-VEGFAshRNA or L-VEGF164shRNA compared to control. Erythropoietin (EPO), brain-derived neurotrophic factor, glial-derived neurotrophic factor, nerve growth factor, neurotrophin-3 (NT-3) mRNAs were increased in L-VEGFAshRNA, but not L-VEGF164shRNA retinas. In cultured rat Müller cells, knockdown of VEGF upregulated NT-3 and EPO, whereas treatment with EPO activated neuroprotective signaling. Methods to reduce IVNV by selective knockdown of VEGFA, and particularly VEGF 164 , in Müller cells may have fewer deleterious effects than nonselective VEGFA inhibition to all cells in the retina.
Bibliography:ObjectType-Article-1
SourceType-Scholarly Journals-1
ObjectType-Feature-2
content type line 14
content type line 23
ISSN:2045-2322
2045-2322
DOI:10.1038/s41598-018-20278-4