RT Journal Article
SR Electronic
T1 Environmental Oxygen Regulates Astrocyte Proliferation to Guide Angiogenesis during Retinal Development
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 861948
DO 10.1101/861948
A1 Robin M Perelli
A1 Matthew L O’Sullivan
A1 Samantha Zarnick
A1 Jeremy N Kay
YR 2020
UL http://biorxiv.org/content/early/2020/05/09/861948.abstract
AB Transient neonatal exposure to high oxygen levels is a major risk factor for retinopathy of prematurity (ROP), a disease of perturbed retinal vascular development. The factors that interrupt normal angiogenesis following oxygen exposure remain unclear. Formation of retinal vasculature requires guidance cues from astrocytes, suggesting that astrocyte disturbances could contribute to oxygen-induced retinopathy. However, it is presently unknown whether environmental oxygen influences astrocyte development. To investigate this question we raised neonatal mice in hyperoxic conditions (75% O2) from postnatal day 0-4, during astrocyte network formation. We found that hyperoxia suppressed proliferation of retinal astrocytes, whereas return to room air at P4 induced a major astrocyte proliferative response, massively increasing astrocyte numbers and disturbing their spatial patterning prior to arrival of developing vasculature. This treatment paradigm also disrupted vascular development in a manner reminiscent of ROP, leading to vitreous hemorrhage and neuroretina defects. Moreover, within individual animals, the severity of vascular phenotypes was strongly correlated with the number of excess astrocytes. Direct exposure to hypoxia (10% O2) produced similar effects, indicating that developing astrocytes are sensitive to relative decrements in oxygen availability. Molecular analysis revealed that the proliferative response was blunted in mice bearing an astrocyte-specific ablation of the HIF2α transcription factor. Together, our results support a model in which neonatal astrocytes use a HIF2α-dependent pathway to sense oxygen levels, thereby regulating the number of astrocytes within the angiogenic template. In this model, fluctuations in environmental oxygen can become pathogenic when they over-stimulate this proliferation control mechanism, leading to excess astrocytes that interfere with retinal angiogenesis.Competing Interest StatementThe authors have declared no competing interest.