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Dallas Shujing Shi, Ashlie Bernhisel, Patrick Kamba, Ashley Brown, Camille Fung, M Elizabeth Hartnett; A Model for Studying ROP in IUGR. Invest. Ophthalmol. Vis. Sci. 2016;57(12):6284.
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© ARVO (1962-2015); The Authors (2016-present)
Infants with intrauterine growth restriction (IUGR) are known to be susceptible to developing retinopathy of prematurity (ROP), yet no animal model mimicking the most common etiology of IUGR has been used to study ROP. Here, we use maternal infusion of a thromboxane A2-analog in mice during the last week of gestation to mimic human pregnancy-induced hypertension, a common cause of IUGR. We test the hypothesis that IUGR pups would exhibit abnormal retinal vascular development after birth compared to pups from sham-operated dams.
Matings of C57BL/6J mice were set up. At E12.5, pregnant females were anesthetized with ketamine (40 ug/g) and xylazine (8 ug/g). Then, a 1-cm incision was made over the right hip. Micro-osmotic pumps (Durect Corportation) containing vehicle (0.5% ethanol for sham group) or 2000ng/h of U-46619 (Cayman Chemical) were implanted retroperitoneally through the incision. Dams were allowed to deliver spontaneously. On day 5, a cohort of sham and IUGR mice were weighted, euthanized, and retinas dissected. A separate cohort of animals was placed though the oxygen-induced retinopathy (OIR) model (Smith el al. 1994). All dissected retinas were fixed, stained with isolectin, flatmounted, and imaged. Avascular areas and neovascular tufts were quantified and analyzed using student t-tests.
IUGR pups weighed 12% less on postnatal day 5 compared to shams (n = 8, P = 0.04). At baseline on postnatal day 5, IUGR pups showed abnormal vessel development with a paucity of branched vessels but with further vessel migration. A 9-fold increase in neovascular tufts was observed in IUGR mice retinas on postnatal day 5 compared to sham controls (N = 3, P = 0.0061). Hyperbaric oxygen exposure similarly resulted in an increase in neovasular tufts in IUGR pups compared to controls (mean = 18.7% in sham vs. 28.9% in IUGR retinas, n = 5, P = 0.0127). Total avascular areas was not significantly different between the OIR groups but was decreased in baseline postnatal day 5 IUGR pups (37.2% in sham vs. 13.2% in IUGR retinas, n =3, P = 0.0351).
Our results allows for animal interrogation into the molecular mechanisms of IUGR-induced ROP. We demonstrate that an in utero hypoxic environment produced by pregnancy-induced hypertension paves the way for pathological retinal vessel growth after birth. This abnormality is compounded by a secondary postnatal hyperoxic challenge and reflects neovascular changes typically seen in human ROP.
This is an abstract that was submitted for the 2016 ARVO Annual Meeting, held in Seattle, Wash., May 1-5, 2016.
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