Roles of HIFs and VEGF en angiogenesis in the retina and brain
Roles of HIFs and VEGF en angiogenesis in the retina and brain
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DOI：
10.1172/jci126655
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发表时间：
2019-09-03
影响因子：
15.9
通讯作者：
Nathans, Jeremy
中科院分区：
文献类型：
--
作者：
Rattner, Amir;Williams, John;Nathans, Jeremy
哺乳动物视网膜中的血管发育通常是CNS血管发育的范例，其研究揭示了解释抗血管生成疗法在视网膜血管疾病中的功效的基本机制。在哺乳动物视网膜的发育过程中，缺氧星形胶质细胞被假设分泌VEGF，当它们从视盘径向迁移时，VEGF吸引生长的内皮细胞。然而，在发育中的小鼠视网膜中使用星形胶质细胞特异性缺失VEGF的这种模型的已发表测试似乎与这一理论相矛盾。在这里，我们报告说，选择性地消除VEGF在新生儿视网膜星形胶质细胞与Gfap-Cre线，重组效率约为100%，对星形胶质细胞的增殖或径向迁移没有影响，但完全阻断径向迁移的内皮细胞，强烈支持缺氧星形胶质细胞模型。使用额外的Cre驱动线，我们发现了视网膜衍生的（旁分泌）和星形胶质细胞衍生的（自分泌）VEGF在控制星形胶质细胞增殖和迁移中的基本和部分冗余作用的证据。我们还扩展了以前的研究，表明视网膜神经元中的HIF-1 α和Muller胶质细胞中的HIF-2 α在视网膜血管发育和疾病中起着不同的作用，增加了越来越多的数据，这些数据表明这2种缺氧感应转录因子的专业化。
Vascular development in the mammalian retina is a paradigm for CNS vascular development in general, and its study is revealing fundamental mechanisms that explain the efficacy of antiangiogenic therapies in retinal vascular disease. During development of the mammalian retina, hypoxic astrocytes are hypothesized to secrete VEGF, which attracts growing endothelial cells as they migrate radially from the optic disc. However, published tests of this model using astrocyte-specific deletion of Vegf in the developing mouse retina appear to contradict this theory. Here, we report that selectively eliminating Vegf in neonatal retinal astrocytes with a Gfap-Cre line that recombines with approximately 100% efficiency had no effect on proliferation or radial migration of astrocytes, but completely blocked radial migration of endothelial cells, strongly supporting the hypoxic astrocyte model. Using additional Cre driver lines, we found evidence for essential and partially redundant actions of retina-derived (paracrine) and astrocyte-derived (autocrine) VEGF in controlling astrocyte proliferation and migration. We also extended previous studies by showing that HIF-1 alpha in retinal neurons and HIF-2 alpha in Muller glia play distinct roles in retinal vascular development and disease, adding to a growing body of data that point to the specialization of these 2 hypoxia-sensing transcription factors.