Retinopathy of prematurity is a sight-threatening complication of
premature birth caused by nitro-oxidative insult to the developing retinal vasculature during therapeutic
hyperoxia exposure and later
ischemia-induced neovascularization on supplemental
oxygen withdrawal. In the vasodegenerative phase, during
hyperoxia, defective
endothelial nitric oxide synthase (NOS) produces reactive
oxygen and
nitrogen free radicals rather than vasoprotective
nitric oxide for unclear reasons. Crucially, normal NOS function depends on availability of the cofactor (6R)-5,6,7,8-tetrahydrobiopterin (BH4). Because BH4 synthesis is controlled enzymatically by
GTP cyclohydrolase (GTPCH), we used GTPCH-depleted mice [hyperphenylalaninemia strain (hph1)] to investigate the impact of
hyperoxia on BH4 bioavailability and
retinal vascular pathology in the neonate.
Hyperoxia decreased BH4 in retinas, lungs, and aortas in all experimental groups, resulting in a dose-dependent decrease in NOS activity and, in the wild-type group, elevated NOS-derived
superoxide.
Retinal dopamine levels were similarly diminished, consistent with the dependence of
tyrosine hydroxylase on BH4. Despite greater depletion of BH4, the hph(+/-) and hph1(-/-) groups did not show exacerbated
hyperoxia-induced vessel closure, but exhibited greater vascular protection and reduced progression to neovascular disease. This vasoprotective effect was independent of enhanced circulating
vascular endothelial growth factor (
VEGF), which was reduced by
hyperoxia, but to local retinal ganglion cell layer-derived
VEGF. In conclusion, a constitutively higher level of
VEGF expression associated with
retinal development protects GTPCH-deficient neonates from
oxygen-induced vascular damage.