Down-regulation of vascular endothelial growth factor (VEGF) and its receptors during supplemental O2 administration in preterm infants leads to vaso-obliteration of the immature retina. Recovery in room air stimulates VEGF overproduction, causing vasoproliferation and neovascularization. Pigment epithelium-derived factor (PEDF) is antiangiogenic, is up-regulated by hyperoxia, and plays a role in retinal development. We examined the hypothesis that repeated cycles of hyperoxia with brief episodes of hypoxia (simulating oxygen fluctuations seen in preterm infants) lead to altered retinal VEGF and PEDF expression prior to room air recovery. At birth (P0), newborn rats were exposed to alternating cycles of 50% oxygen with brief episodes of 12% oxygen for 7 and 14 days. Rats were sacrificed immediately following 7-day (7DO2) or 14-day (14DO2) hyperoxia or allowed to recover in room air until P21 (7DO2/14DRA and 14DO2/7DRA). Room air littermates were sacrificed at P7 (7DRA), P14 (14DRA), and P21 (21DRA). Retinal vasculature, VEGF protein, VEGF isoforms, VEGF receptors, and PEDF messenger ribonucleic acid (mRNA) expression were examined. All hyperoxia-exposed retinas displayed evidence of neovascularization with “plus disease.” Retinal VEGF protein was elevated in all hyperoxia exposed groups. VEGF164 was the predominant splice variant expressed in the retina and was suppressed in the 7DO2 (p < .01) and 7DO2/14DRA (p < .05) groups. In contrast, VEGF164 was up-regulated in the 14DO2 (p < .0007) and 14DO2/7DRA (p < .05) groups. Similarly, VEGFR-2 mRNA expression was elevated in the 14DO2 versus 14DRA groups (p < .05) and in the 14DO2/7DRA versus 14DRA (.001) and 7DO2/14DRA (p < .01) groups. Coexpression of VEGFR-2 and neuropilin 1 was higher in the recovery groups (p < .01). PEDF transcripts were higher in the 14DO2/7DRA only (p < .01). Brief episodes of hypoxia during hyperoxia result in retinal VEGF overproduction and neovascularization before recovery in room air. This finding suggests that preterm infants who experience frequent O2 fluctuations during long-term hyperoxia may have retinal VEGF overproduction prior to weaning from supplemental O2 therapy.
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