title: Prolyl hydroxylase domain protein 2 (PHD2) mediates oxygen-induced retinopathy in neonatal mice.
abstract: Retinopathy of prematurity is a major side effect of oxygen therapy for preterm infants, and is a leading cause of blindness in children. To date, it remains unclear whether the initial microvascular obliteration is triggered by degradation of hypoxia inducible factor (HIF) α proteins or by other mechanisms such as oxidative stress. Here we show that prolyl hydroxylase domain protein 2 (PHD2), an enzyme mostly responsible for oxygen-induced degradation of HIF-α proteins, plays a major role in oxygen-induced retinopathy in mice. In neonatal mice expressing normal amounts of PHD2, exposure to 75% oxygen caused significant degradation of retinal HIF-α proteins, accompanied by massive losses of retinal microvessels. PHD2 deficiency significantly stabilized HIF-1α, and to some extent HIF-2α, in neonatal retinal tissues, and protected retinal microvessels from oxygen-induced obliteration. After hyperoxia-treated neonatal mice were returned to ambient room air, retinal vasculature in PHD2-deficient mice remained mostly intact and showed very little neoangiogenesis. These findings demonstrate a close association between PHD2-dependent HIF-α degradation and oxygen-induced retinal microvascular obliteration, and imply that PHD2 may be a promising therapeutic target to prevent oxygen-induced retinopathy.
authors: Center for Vascular Biology, Department of Cell Biology, University of Connecticut Health Center, Farmington, CT 06030-3501, USA.
authors: Li-Juan
authors: LJ
authors: Duan
authors: Kotaro
authors: K
authors: Takeda
authors: Guo-Hua
authors: GH
authors: Fong
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D001253:Astrocytes / Q000378:metabolism; D018496:Hyperoxia / Q000378:metabolism; D000860:Hypoxia; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism; D064799:Hypoxia-Inducible Factor-Proline Dioxygenases; D007150:Immunohistochemistry / Q000379:methods; D051379:Mice; D018345:Mice, Knockout; D010100:Oxygen / Q000378:metabolism*; D020286:Pericytes / Q000378:metabolism; D011393:Procollagen-Proline Dioxygenase / Q000378:metabolism / Q000502:physiology*; D017434:Protein Structure, Tertiary; D012164:Retinal Diseases / Q000378:metabolism*; D012171:Retinal Vessels / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction
chemical_list: D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D011393:Procollagen-Proline Dioxygenase; C490189:Egln1 protein, mouse; D064799:Hypoxia-Inducible Factor-Proline Dioxygenases; D010100:Oxygen