Hyperoxia causes regression of vitreous neovascularization by downregulating VEGF/VEGFR2 pathway

Hua Liu, Wenbo Zhang, Zhimin Xu, Robert William Caldwell, Ruth B Caldwell, Steven E. Brooks

Research output: Contribution to journalArticle

17 Citations (Scopus)

Abstract

Purpose. Neovascularization (NV) is a sight-threatening complication of retinal ischemia in diabetes, retinal vein occlusion, and retinopathy of prematurity. Current treatment modalities, including laser photocoagulation and repeated intraocular injection of VEGF antagonists, are invasive and not always effective, and may carry side effects. We studied the use of hyperoxia as an alternative therapeutic strategy for regressing established vitreous NV in a mouse model of oxygen-induced ischemic retinopathy. Methods. Hyperoxia treatment (HT, 75% oxygen) was initiated on postnatal day (P)17 after the onset of vitreous NV. Immunohistochemistry and quantitative PCR were used to assess retinal vascular changes in relation to apoptosis, and expression of VEGFR2 and inflammatory molecules. Effects of intravitreal injections of VEGF-A, VEGF-E, PlGF-1, and VEGF trap were also studied. Results. HT selectively reduced NV by 70% within 24 hours. It robustly increased the level of cleaved caspase-3 in the vitreous NV between 6 and 18 hours and promoted infiltration of macrophage/microglial cells. The HT-induced apoptosis was preceded by a significant reduction in VEGFR2 expression within the NV and an increase in VEGFR2 within the surrounding neural tissue. Intravitreal VEGF-A and VEGF-E (VEGFR2 agonist) but not PlGF-1 (VEGFR1 agonist) prevented HT-induced apoptosis and regression of NV. In contrast, VEGF trap and VEGFR2 blockers mimicked the effect of HT. However, intravitreal VEGF trap induced increases in inflammatory molecules while HT did not have such unwanted effect. Conclusions. HT may be clinically useful to specifically treat proliferative NV in ischemic retinopathy.

Original languageEnglish (US)
Pages (from-to)918-931
Number of pages14
JournalInvestigative Ophthalmology and Visual Science
Volume54
Issue number2
DOIs
StatePublished - Feb 1 2013

Fingerprint

Hyperoxia
Vascular Endothelial Growth Factor A
Down-Regulation
Apoptosis
Intraocular Injections
Oxygen
Retinal Vein Occlusion
Retinal Vessels
Retinopathy of Prematurity
Intravitreal Injections
Light Coagulation
Caspase 3
Lasers
Therapeutics
Ischemia
Immunohistochemistry
Macrophages
Polymerase Chain Reaction
aflibercept

ASJC Scopus subject areas

  • Ophthalmology
  • Sensory Systems
  • Cellular and Molecular Neuroscience

Cite this

Hyperoxia causes regression of vitreous neovascularization by downregulating VEGF/VEGFR2 pathway. / Liu, Hua; Zhang, Wenbo; Xu, Zhimin; Caldwell, Robert William; Caldwell, Ruth B; Brooks, Steven E.

In: Investigative Ophthalmology and Visual Science, Vol. 54, No. 2, 01.02.2013, p. 918-931.

Research output: Contribution to journalArticle

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abstract = "Purpose. Neovascularization (NV) is a sight-threatening complication of retinal ischemia in diabetes, retinal vein occlusion, and retinopathy of prematurity. Current treatment modalities, including laser photocoagulation and repeated intraocular injection of VEGF antagonists, are invasive and not always effective, and may carry side effects. We studied the use of hyperoxia as an alternative therapeutic strategy for regressing established vitreous NV in a mouse model of oxygen-induced ischemic retinopathy. Methods. Hyperoxia treatment (HT, 75{\%} oxygen) was initiated on postnatal day (P)17 after the onset of vitreous NV. Immunohistochemistry and quantitative PCR were used to assess retinal vascular changes in relation to apoptosis, and expression of VEGFR2 and inflammatory molecules. Effects of intravitreal injections of VEGF-A, VEGF-E, PlGF-1, and VEGF trap were also studied. Results. HT selectively reduced NV by 70{\%} within 24 hours. It robustly increased the level of cleaved caspase-3 in the vitreous NV between 6 and 18 hours and promoted infiltration of macrophage/microglial cells. The HT-induced apoptosis was preceded by a significant reduction in VEGFR2 expression within the NV and an increase in VEGFR2 within the surrounding neural tissue. Intravitreal VEGF-A and VEGF-E (VEGFR2 agonist) but not PlGF-1 (VEGFR1 agonist) prevented HT-induced apoptosis and regression of NV. In contrast, VEGF trap and VEGFR2 blockers mimicked the effect of HT. However, intravitreal VEGF trap induced increases in inflammatory molecules while HT did not have such unwanted effect. Conclusions. HT may be clinically useful to specifically treat proliferative NV in ischemic retinopathy.",
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