Astrocytes sense oxygen to guide angiogenesis Free

Retinal vascularisation is dependent on cues from glial cells called astrocytes that guide endothelial cell growth. Disrupted vascularisation causes retinopathy of prematurity (ROP), a disorder that can lead to blindness and is characterised by the failure of vessels to spread fully through the retina. Risk factors for ROP include high oxygen levels during vascularisation, but why the vasculature does not resume expansion when oxygen levels return to normal remains an unresolved problem. Using a mouse model, Robin Perelli, Matthew O'Sullivan, Samantha Zarnick and Jeremy Kay now implicate astrocytes in oxygen-induced retinopathy. The authors first show that neonatal hyperoxia between P0 and P4 delays the vascular wave front and leads to vitreous haemorrhages, a persistent hyaloid system and abnormal vascular morphology; severe retinal abnormalities are also observed longer term. Although astrocyte colonisation of the retina is not affected by hyperoxia, after returning to normal oxygen levels, astrocyte numbers substantially increase via proliferation in the retina. Astrocyte patterning is also defective, showing irregular arrangements which endothelial tip cells strictly follow; indeed, astrocyte number predicts the severity of the vascular abnormalities. Astrocytes can also be stimulated to overproliferate with neonatal hypoxia. Finally, the authors show that astrocyte proliferation in response to lower oxygen levels is mediated by HIF signalling and the HIF effector HIF2α. This work suggests that fluctuating oxygen levels might underlie the vascular abnormalities of ROP via aberrant astrocyte proliferation.