Abstract
Purpose :
Two major complications that affect the outcomes of prematurity during perinatal period are retinopathy of prematurity (ROP), and periventricular leukomalacia (PVL). The goal of this study is to test our hypothesis that hyperoxia down regulates VEGF and induces global cerebral vaso-obliteration of immature vessels that leads to ischemia of immature tissues and it is the common pathophysiology for ROP and PVL.
Methods :
Animal model of oxygen induced retinopathy in mice were generated by exposing 7 days old (P7) FVB mice to 95% O2 for 5 days then returning to room air (RA). Animals were examined at P12, P18 and P30. In vivo 3D-micro MRI images and angiography of mice were obtained using lyposomal SC-Gd (19m MGD) as a nanoparticle MRI contrast agent with a Bruker Biospec MRI system. The Inveon micro PET imaging system was used to study brain and ocular tissue glucose uptake using 2-deoxy-2-[fluorine-18]fluoro- D-glucose (18F-FDG). Immunohistology study was done on both ocular and brain tissues.
Results :
After exposure to high O2 for 5 days, 3D in vivo MRI angiography showed global vaso-obliteration and ablation of both cerebral and ocular vessels. The significant changes occurred to the cerebral small vessels and Circle of Willis. The density of ocular and crerebral blood vessels in oxygen treated group was about 50 to 60% less than that of animals in RA. At P19, there were significant neovascularization in both brain and eyes, however majority of these new vessels showed discontinuation of contrast agent. MRI T2 imaging showed edematic changes of cortex special surrounding the ventricles, hippocampus and corpus callosum at P18. Glucose uptakes were significantly increased in brain and ocular tissues 5 days after oxygen treatment in comparison to control groups. It continued to increase and reached peak at P19, about 50% more than that in control animals and remained at similar level up to P30. IHC staining showed increase expression of HIF-1a and decrease expression of VEGF at P12.
Conclusions :
Hyperoxia resulted in down regulation of VEGF and global vaso-obliteration in both eyes and brain leading to tissue hypoxia and increase of glycolysis. The blood vessels including density and anatomy were abnormal for at least 3 weeks after animal were returned to room air. Further studies are necessary with regard to the role of glycolysis in the development of ROP and PVL.
This is an abstract that was submitted for the 2016 ARVO Annual Meeting, held in Seattle, Wash., May 1-5, 2016.