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V.S. Hau, B. Carter, M. Dahl, L. Dong, K. Howes, K. Albertine, K. Zhang; A Novel Animal Model for the Study of Retinopathy of Prematurity . Invest. Ophthalmol. Vis. Sci. 2006;47(13):3227.
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Many illnesses in preterm infants, including retinopathy of prematurity (ROP), bronchopulmonary dysplasia (BPD), intraventricular hemorrhage (IVH), and brain injury occur in response to oxygen treatments and mechanical ventilation. Unlike adults, the newborn infant is unable to regulate the excessive oxygen delivery in the underdeveloped retinal vasculature. ROP occurs in two distinct steps: 1) excessive oxygen treatment inhibits proper development of the retinal vasculature, which is followed by 2) uncontrolled proliferative growth of retinal blood vessels in response to the resultant neural retinal ischemia and hypoxia. Prematurely delivered lambs (125–130d gestation; term=147d) have proven to be an excellent model for studying BPD (Albertine et al., AJRCCM 159:945–958, 1999). We will utilize this animal model to study vascular growth factor and receptor regulation during the stages of ROP. FZD4 and its ligand, Norrie, have been recently identified as important mediators of normal retinal vascularization. Therefore, another important objective of this study is to examine altered expression of these proteins in this ROP model.
For ROP studies, lambs will be delivered at a stage coinciding with retinal vascular development and exposed to hyperoxic conditions to induce vaso–obliteration and cessation of normal retinal blood vessel development (consistent with the first stage of ROP). The lambs will then be returned to normoxic conditions, thereby inducing hypoxia and resultant neovascularization, the second stage of ROP and other retinopathies. Preterm lambs are managed for 72h by conventional mechanical ventilation. During resuscitation, the lambs are treated with 100% oxygen, and then gradually weaned to maintain arterial PO2 between 60 and 70 mmHg. Eyes will be fixed in 4% paraformaldehyde, and prepared for cryostat sectioning according to standard techniques. Immunohistochemistry (using antibodies tested for monospecificity) for growth factors and their receptors including VEGF, Flk–1, FZD4 and Norrie will be performed on eyes from lambs rendered hyperoxic and hypoxic.
We are currently characterizing normal growth factor and receptor expression patterns in retinal development and vascularization in preterm and full term lambs.
This animal model will provide an important resource for examining altered regulation of the Wnt receptor, FZD4, and its ligand, and VEGF and its receptors during normal angiogenesis in the molecular pathology of ROP in preterm infants.
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