Environmental oxygen regulates astrocyte proliferation to guide angiogenesis during retinal development

Abstract

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 excess oxygen – disrupts formation of the angiogenic astrocyte template. Exposing newborn mice to elevated oxygen (75%) suppressed astrocyte proliferation, whereas return to room air (21% oxygen) at postnatal day 4 triggered extensive proliferation, massively increasing astrocyte numbers and disturbing their spatial patterning prior to the arrival of developing vasculature. Proliferation required astrocytic HIF2α and was also stimulated by direct hypoxia (10% oxygen), 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.

Loss of Tbx3 in mouse eye causes retinal angiogenesis defects reminiscent of human disease

“…In contrast, the Tbx3 cKO has a persistent hyaloid artery as well as a hypovascular retina. Along with FEVR, these phenotypes are also present in a mouse model of Retinopathy of Prematurity, in which neonatal pups are exposed to elevated oxygen levels from P0 to P4 (Perelli et al, 2021). In these mice, angiogenesis is globally affected, where only about 25% of the entire retinal surface was covered by P8 (Perelli et al, 2021).…”

“…Along with FEVR, these phenotypes are also present in a mouse model of Retinopathy of Prematurity, in which neonatal pups are exposed to elevated oxygen levels from P0 to P4 (Perelli et al, 2021). In these mice, angiogenesis is globally affected, where only about 25% of the entire retinal surface was covered by P8 (Perelli et al, 2021). In comparison, vessels covered approximately 25% of the dorsal Tbx3 cKO retina.…”

“…60 In these mice, angiogenesis is globally affected, where only about 25% of the entire retinal surface was covered by P8. 60 In comparison, vessels covered approximately 25% of the dorsal Tbx3 cKO retina. Therefore, it is possible that Tbx3 is required for the hypoxia signaling pathway either in neurons or in astrocytes.…”

Retinoic acid signaling in mouse retina endothelial cells is required for early angiogenic growth

“…Pericytes are potential candidate since they are known to play a role in maintaining the BRB (32). Astrocytes have high RA signaling activity in the retina based on expression of the RARE-lacZ genetic reporter (33) and are well known to play a role in retinal angiogenesis and BRB integrity (17,33,34). Further, RA has different roles in the brain versus the retina vasculature development, however, more studies are needed to parse out how RA signaling regulates brain versus retina endothelial cells.…”

Tailless and hypoxia inducible factor-2α cooperate to sustain proangiogenic states of retinal astrocytes in neonatal mice

“…During the subsequent week or so, the vascular network expands radially, reaching the retinal periphery by postnatal day (P) 7-8 ( Duan et al, 2017 ; Fruttiger, 2002 ; Gariano et al, 1996 ; Gerhardt et al, 2003 ; Hellström et al, 2007 ; Stone and Dreher, 1987 ). Besides endothelial cells (ECs), astrocytes are also critical for retinal vascular development ( Duan et al, 2017 ; Gariano et al, 1996 ; Paisley and Kay, 2021 ; Perelli et al, 2021 ; Stone and Dreher, 1987 ; Tao and Zhang, 2014 ).…”