Environmental Oxygen Regulates Astrocyte Proliferation to Guide Angiogenesis during Retinal Development

Angiogenesis in the developing mammalian retina requires patterning cues from astrocytes. Developmental disorders of retinal vasculature, such as retinopathy of prematurity (ROP), involve arrest or mispatterning of angiogenesis. Whether these vascular pathologies involve astrocyte dysfunction remains untested. Here we demonstrate that the major risk factor for ROP - transient neonatal exposure to hyperoxia - disrupts formation of the angiogenic astrocyte template. Exposing mice to hyperoxia (75% O2) from postnatal day (P)0-4 suppressed astrocyte proliferation, while return to room air (21% O2) at P4 triggered extensive proliferation, massively increasing astrocyte numbers and disturbing their spatial patterning prior to arrival of developing vasculature. Proliferation required astrocytic HIF2 and was also stimulated by direct hypoxia (10% O2), suggesting that astrocyte oxygen sensing regulates the number of astrocytes produced during development. Along with astrocyte defects, return to room air also caused vascular defects reminiscent of ROP. Strikingly, these vascular phenotypes were more severe in animals that had larger numbers of excess astrocytes. Together, our findings suggest that fluctuations in environmental oxygen dysregulate molecular pathways controlling astrocyte proliferation, thereby generating excess astrocytes that interfere with retinal angiogenesis.