Open AccessDevelopmental vascular pruning in neonatal mouse retinas is programmed in the astrocytic oxygen sensing mechanism
Author(s) -
Li Duan,
GuoHua Fong
Publication year - 2019
Publication title -
development
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 3.754
H-Index - 325
eISSN - 1477-9129
pISSN - 0950-1991
DOI - 10.1242/dev.175117
Subject(s) - biology , retinal , microbiology and biotechnology , hypoxia inducible factors , vascular endothelial growth factor a , vascular endothelial growth factor , hypoxia (environmental) , population , astrocyte , neuroscience , biochemistry , cancer research , oxygen , central nervous system , vegf receptors , chemistry , gene , organic chemistry , demography , sociology
Vascular pruning is critical to normal development, but its underlying mechanisms are poorly understood. Here we report that retinal vascular pruning is controlled by the oxygen sensing mechanism in local astrocytes. Oxygen sensing is mediated by prolyl hydroxylase domain proteins (PHDs), which use O2 as a substrate to hydroxylate specific prolyl residues on hypoxia inducible factor (HIF)-α proteins, labelling them for polyubiquitination and proteasomal degradation. In neonatal mice, astrocytic PHD2 deficiency led to elevated HIF-2α protein levels, expanded retinal astrocyte population, and defective vascular pruning. While astrocytic VEGF-A was also increased, anti-VEGF failed to rescue vascular pruning. On the other hand, stimulation of retinal astrocytic growth by intravitreal delivery of PDGF-A was sufficient to block retinal vascular pruning in wild-type mice. We propose that in normal development, oxygen from nascent retinal vasculature triggers PHD2 dependent HIF-2α degradation in nearby astrocytic precursors, thus limiting their further growth by driving them to differentiate into non-proliferative mature astrocytes. The physiological limit of retinal capillary density may be set by astrocytes available to support their survival, with excess capillaries destined for regression.