VEGF-mediated STAT3 activation inhibits retinal vascularization by down-regulating local erythropoietin expression.

Abstract

Avascular, hypoxic retina has been postulated to be a source of angiogenic factors that cause aberrant angiogenesis and intravitreal neovascularization (IVNV) in retinopathy of prematurity. Vascular endothelial growth factor (VEGF) is an important factor involved. However, VEGF is also required for normal retinal vascular development, which raises concerns about inhibiting its activity to treat IVNV in retinopathy of prematurity. Therefore, understanding the effects that VEGF has on other factors in the development of avascular retina is important to prevent aberrant angiogenesis and IVNV. Here, we show that STAT3 was activated by increased retinal VEGF in the rat 50/10 oxygen-induced retinopathy model. Phospho-STAT3 colocalized with glutamine synthetase-labeled Müller cells. Inhibition of STAT3 reduced avascular retina and increased retinal erythropoietin (Epo) expression. Epo administered exogenously also reduced avascular retina in the model. In an in vitro study, hypoxia-induced VEGF inhibited Epo gene expression by STAT3 activation in rat Müller cells. The mechanism by which activated STAT3 regulated Epo was by inhibition of Epo promoter activity. Together, these findings show that increased retinal VEGF contributes to avascular retina by regulating retinal Epo expression through Janus kinase/STAT signaling. Our results suggest that rescuing Epo expression in the retina before the development of IVNV may promote normal developmental angiogenesis and, therefore, reduce the stimulus for later pathologic IVNV.

• Authors: Haibo Wang, Grace Byfield, Yanchao Jiang, George Wesley Smith, Manabu McCloskey, M Elizabeth Hartnett
• Journal: The American journal of pathology (Am J Pathol) Vol. 180 Issue 3 Pg. 1243-1253 (Mar 2012) ISSN: 1525-2191 [Electronic] United States
• PMID: 22230249 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2012 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.

Chemical References

• STAT3 Transcription Factor
• Vascular Endothelial Growth Factor A
• Erythropoietin
• Janus Kinases
• Caspase 3
• Oxygen

Topics

• Animals
• Animals, Newborn
• Caspase 3 (metabolism)
• Down-Regulation
• Erythropoietin (administration & dosage, metabolism, pharmacology)
• Janus Kinases (metabolism)
• Oxygen (administration & dosage)
• Rats
• Rats, Sprague-Dawley
• Retinal Neovascularization (prevention & control)
• STAT3 Transcription Factor (metabolism)
• Signal Transduction (physiology)
• Vascular Endothelial Growth Factor A (physiology)