Environmental oxygen regulates astrocyte proliferation to guide angiogenesis during retinal development.
Environmental oxygen regulates astrocyte proliferation to guide angiogenesis during retinal development.
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DOI：
10.1242/dev.199418
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发表时间：
2021-05-01
期刊：
影响因子：
--
通讯作者：
Kay JN
中科院分区：
文献类型：
--
作者：
Perelli RM;O'Sullivan ML;Zarnick S;Kay JN
发育中的哺乳动物视网膜中的血管生成需要来自星形胶质细胞的图案线索。视网膜血管系统发育障碍，例如早产儿视网膜病变（ROP），涉及血管生成的停滞或错误模式。这些血管病变是否涉及星形胶质细胞功能障碍仍有待检验。在这里，我们证明了ROP的主要危险因素-短暂的新生儿暴露于过量的氧气-破坏了血管生成星形胶质细胞模板的形成。将新生小鼠暴露于高氧（75%）抑制星形胶质细胞增殖，而在出生后第4天返回室内空气（21%氧气）引发广泛增殖，大量增加星形胶质细胞数量并在发育中的血管系统到来之前扰乱其空间模式。增殖需要星形胶质细胞HIF 2 α，并且也受到直接缺氧（10%氧气）的刺激，这表明星形胶质细胞氧传感调节发育过程中产生的星形胶质细胞数量。沿着星形胶质细胞缺陷，回到室内空气也会引起血管缺陷，使人联想到ROP。引人注目的是，这些血管表型在具有大量过量星形胶质细胞的动物中更为严重。总之，我们的研究结果表明，环境中的氧气波动失调控制星形胶质细胞增殖的分子途径，从而产生过量的星形胶质细胞，干扰视网膜血管生成。 氧调节未成熟视网膜星形胶质细胞的增殖。扰乱这一机制会使星形胶质细胞数量增加，破坏视网膜血管生成，并导致类似早产儿视网膜病变的血管病变。
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. Oxygen regulates proliferation of immature retinal astrocytes. Perturbing this mechanism inflates astrocyte numbers, disrupts retinal angiogenesis and leads to vascular pathologies resembling retinopathy of prematurity.
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