Insulin-like growth factors (IGFs) are potent mitogens for many cells types, including endothelial cells. In a mouse model of retinal neovascularization, we have shown previously that there is a temporal and spatial relationship between IGF-II gene expression and neovascularization, suggesting that IGF-II is acting as an angiogenic factor. Since IGF action is modulated by a family of IGFBPs (1-6), we hypothesized that the IGFBPs also play a role in retinal angiogenesis. To determine the temporal relationship between IGFBP gene expression and retinal neovascularization, we induced retinopathy in C57BL/6J mice by exposure to 75% oxygen for 5 days, between postnatal days 7 to 12, followed by room air for either 12 hours, 36 hours, 5 days or 18 days. Control litter mates of the same age were reared in room air. The relative abundance of IGFBP mRNAs was analyzed in total RNA from whole eyes by Northern blot analysis using 32P-labeled cDNA probes, and was quantified on a phosphorimager. IGFBP-2, -4 and -5 mRNA abundance increased 1.5-, 1.5- and 2.5-fold, respectively, in the eyes after exposure to hyperoxia for 5 days, as compared to the control group. At the time of peak neovascularization (following the return to room air for 5 days), IGFBP-2 and-5 mRNA abundance increased 2-fold and 4.3-fold, respectively. IGFBP-4 mRNA abundance showed a biphasic response following the return to room air. It decreased to 0.6-fold at 36 hours and increased to 1.6- and 2.5- fold, at 5 and 18 days, respectively. IGFBP-3 and -6 mRNA abundance was low among all groups. IGFBP-1 mRNA was not detected. These results suggest that IGFBP-2, -4 and -5 may be modulating the actions of IGF-II in the process of retinal angiogenesis and may be playing a role in the pathogenesis of retinopathy of prematurity.

(Supported by MRC Canada & the Pooled Res. Trust Fund of the LRI.)