Insulin-like growth factor I (IGF-I) is necessary for vascular growth in the neonatal retina by acting as a permissive factor for vascular endothelial growth factor (VEGF) angiogenic activity. Low IGF-I levels in serum from extremely premature newborn infants were found to be predictive for retinopathy of prematurity (ROP). Soluble VEGFR-1 (sVEGFR-1) blocks VEGF activity by binding VEGF and preventing activation of its receptors. We examined the relationship of serum and vitreous VEGF, sVEGFR-1, and IGF-I in rats exposed to repeated cycles of hyperoxia with brief episodes of hypoxia (simulating oxygen fluctuations seen in preterm infants). At birth (P0), newborn rats were exposed to alternating cycles of 50% oxygen followed by 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; and serum and vitreous levels of VEGF, sVEGFR-1, and IGF-I were examined. All hyperoxia-exposed retinas displayed evidence of neovascularization with “plus disease.” In the serum, VEGF levels (pg/mL) were elevated with 7DO2/14DRA (15.4 ± 1.3, p < .05) and 14DO2/7DRA (18.3 ± 1.3, p < .05) versus 21DRA (10.9 ± 1.5). In contrast, IGF-I levels (ng/mL) were substantially lower with 7DO2/14DRA (283.0 ± 49.2, p < .001) and 14DO2/7DRA (441.0 ± 29.8, p < .001) than 21DRA (1,039.9 ± 114.8). sVEGR-1 was elevated with 7DO2 (465.4 ± 63.4, p < .01) versus control (243.0 ± 51.0). In the vitreous, VEGF levels were suppressed with 7DO2 (45.3 ± 3.3, p < .003) versus (154.7 ± 17.2), coincident with higher sVEGFR-1 levels (3,393.1 ± 804.2, p = NS) versus control (2,153.3 ± 239.9). Vitreous VEGF levels were increased with 14DO2 (398.0 ± 19.7, p < .006) versus control (235.5 ± 23.6). Frequent, brief episodes of hypoxia during long-term exposure to hyperoxia increase VEGF levels in the vitreous prior to recovery in room air. This finding has implications for premature infants who experience frequent fluctuations in PaO2 during supplemental O2 therapy. Further, although our data agree with previous findings that low serum IGF-I levels are associated with ROP, similar deficits are not reflected in the ocular compartment.
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