Hyperoxia depletes (6R)-5,6,7,8-tetrahydrobiopterin levels in the neonatal retina: implications for nitric oxide synthase function in retinopathy.
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.
Centre for Experimental Medicine, Queen's University Belfast, Belfast, United Kingdom.
Kevin S
KS
Edgar
Centre for Experimental Medicine, Queen's University Belfast, Belfast, United Kingdom.
Nuria
N
Matesanz
Centre for Experimental Medicine, Queen's University Belfast, Belfast, United Kingdom.
Tom A
TA
Gardiner
Department of Pharmacology and Anesthesiology, Mayo Clinic, Rochester, Minnesota.
Zvonimir S
ZS
Katusic
Centre for Experimental Medicine, Queen's University Belfast, Belfast, United Kingdom. Electronic address: d.mcdonald@qub.ac.uk.
Denise M
DM
McDonald
D000818:Animals; D001708:Biopterins / Q000031:analogs & derivatives* / Q000378:metabolism; D005260:Female; D018496:Hyperoxia / Q000378:metabolism* / Q000473:pathology; D008297:Male; D051379:Mice; D019001:Nitric Oxide Synthase / Q000378:metabolism*; D012160:Retina / Q000378:metabolism* / Q000473:pathology; D012178:Retinopathy of Prematurity / Q000378:metabolism* / Q000473:pathology; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism
D042461:Vascular Endothelial Growth Factor A; D001708:Biopterins; D019001:Nitric Oxide Synthase; C003402:sapropterin