Effects of Anemia-Induced Retinopathy of Prematurity on Retinal Neuronal Development
Background
Iron-deficiency anemia commonly occurs in premature infants due to frequent phlebotomy and inadequate erythropoiesis, necessitating blood transfusions. Iron deficiency impairs neuronal development and induces hypoxia, overactivating vascular endothelial growth factor (VEGF). This can cause retinopathy of prematurity (ROP) through neovascularization, resulting in retinal detachment and blindness.
It is unknown if iron-deficiency anemia can induce ROP or alter retinal neuronal development.
Objective
To determine the effect of iron-deficiency anemia on retinal angiogenesis and neuronal development.
Methods
Two litters of 22 rat pups were exposed to cyclic hyperoxia-hypoxia under the Penn 50/10 oxygen-induced retinopathy (OIR) model from P0-P14. Rats then recovered in room air until euthanasia at P20. Phlebotomy from P3-P20 induced anemia to a hematocrit of 18% in half the pups. Using qPCR, we measured mRNA expression of molecules indicating retinal iron status (Tfr, Tfrc, Irp2, NCOA4), neuronal development, (BDNF, CREB1), and angiogenesis (Vegfa, Ang1, Ang2, and Tie2). S18 and TBP served as housekeeping genes. The Vegfa to Ang2 ratio was calculated to indicate normal angiogenesis versus neovascularization.. A 2-tail T-test test compared fold change between OIR and OIR+anemia groups.
Results
Tf and TfR were expressed at normal levels (p values = 0.29 and 0.57, respectively). Vegf and Tie2 were upregulated with X-and Y-fold change = 0.68 and 0.79 (p= 0.043 and 0.031, respectively). BDNF and CREB1 were unchanged.
Conclusion
Phlebotomy-induced anemia upregulated Vegf and Tie2, suggesting increased angiogenesis. Both molecules are hypoxia-induced, suggesting anemia may induce retinal hypoxia. Normal retinal iron status in Tf and TfR levels indicate absence of iron deficiency, which may explain why BDNF and CREB1, both iron-sensitive molecules, remained unchanged, despite literature reporting activation in the anemic brain. Our ongoing studies will test the anatomic and functional effects of anemia on retinal development and treatment effects of supplemental iron.