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Originally published In Press as doi:10.1167/iovs.09-3552 on May 27, 2009
 (Investigative Ophthalmology and Visual Science. 2009;50:5364-5374.)
© 2009 by The Association for Research in Vision and Ophthalmology, Inc.
doi:10.1167/iovs.09-3552
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Cellular and Vascular Changes in the Retina of Neonatal Rats after an Acute Exposure to Hypoxia

Charanjit Kaur,1,2 Viswanathan Sivakumar,1 Wallace S. Foulds,2,3,4 Chi D. Luu,2,3,5 and Eng-Ang Ling1

From the Departments of 1Anatomy and 3Ophthalmology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore; 2Singapore Eye Research Institute, Singapore; 4University of Glasgow, Glasgow, Scotland; and 5Centre for Eye Research Australia, University of Melbourne, Royal Victorian Eye and Ear Hospital, East Melbourne, Australia.

Corresponding author: Charanjit Kaur, Department of Anatomy, Yong Loo Lin School of Medicine, Blk MD10, 4 Medical Drive, National University of Singapore, Singapore 117597; antkaurc{at}nus.edu.sg.

Purpose. This study was undertaken to examine the effects of an acute hypoxic exposure on the retinal cells and production of vascular factors such as vascular endothelial growth factor (VEGF) and nitric oxide (NO), which may affect vascular permeability in the developing retina.

Methods. Retinas of 1-day-old rats were examined at 3 hours to 14 days after hypoxic exposure. The mRNA and protein expression of hypoxia-inducible factor-1{alpha} (HIF-1{alpha}), VEGF, endothelial nitric oxide synthase (eNOS), neuronal NOS (nNOS), and inducible NOS (iNOS) were determined by real-time RT-PCR, Western blot analysis, and immunohistochemistry. Electron microscopy was used to examine the structural alterations in retinal cells, and rhodamine isothiocyanate (RhIC) or horseradish peroxidase (HRP) was administered intraperitoneally or intravenously to determine vascular permeability.

Results. The mRNA and protein expression of HIF-1{alpha}, VEGF, eNOS, nNOS, and iNOS, along with VEGF concentration and NO production, were increased in response to hypoxia. Swollen Müller cell processes, apoptotic and necrotic cells in the inner nuclear layer, and changes in ganglion cells such as swollen and disrupted mitochondria were observed in hypoxic animals. Increased leakage of RhIC and HRP from retinal and hyaloid vessels was seen after hypoxic exposure.

Conclusions. The authors suggest that increased VEGF and NO production in hypoxia resulted in increased vascular permeability, leading to changes in Müller cells and degeneration of neural cells. Melatonin administration reduced VEGF and NO production, diminished leakage of RhIC and HRP, and promoted cell proliferation, suggesting this as a potential therapeutic agent in reducing hypoxia-associated damage in the developing retina.






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