DEVELOPMENT OF RETINAL VASCULATURE IS MEDIATED BY HYPOXIA-INDUCED VASCULAR ENDOTHELIAL GROWTH-FACTOR (VEGF) EXPRESSION BY NEUROGLIA
DEVELOPMENT OF RETINAL VASCULATURE IS MEDIATED BY HYPOXIA-INDUCED VASCULAR ENDOTHELIAL GROWTH-FACTOR (VEGF) EXPRESSION BY NEUROGLIA
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DOI：
10.1523/jneurosci.15-07-04738.1995
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发表时间：
1995-07-01
影响因子：
5.3
通讯作者：
KESHET, E
中科院分区：
文献类型：
--
作者：
STONE, J;ITIN, A;KESHET, E
本研究应用原位杂交技术研究了缺氧诱导的血管生成因子血管内皮生长因子（VEGF）在大鼠和新生儿视网膜发育过程中对血管生长的诱导和调控作用。结果表明，VEGF在神经视网膜的最内层（轴突层）和内核层（INL）均有表达，在轴突层，VEGF在星形胶质细胞跨层扩散时瞬时表达，紧接在浅表血管形成之前。在INL中，VEGF由层中间的胞体瞬时表达（大概是穆勒细胞），我们认为，由神经元活动的开始引起的缺氧是通过以下方法检测到的：作为响应，它们分泌VEGF，分别诱导视网膜血管的表层和深层的形成。随着血管变得开放，它们减轻缺氧刺激，因此血管形成与氧需求相匹配。通过三种方式对这一假设进行了实验测试。在新形成的视网膜血管中证实了VEGF的高亲和力flk-1受体的表达，证实了分泌的VEGF以旁分泌方式作用于血管。在星形胶质细胞的原代培养物和神经胶质瘤系的细胞中证实了大胶质细胞对VEGF表达的直接低氧调节，通过显示抑制血管形成的富氧气氛也抑制内源性VEGF产生，证明了在完整发育的视网膜中VEGF表达的低氧调节。
We have studied the role of the hypoxia-inducible angiogenic growth factor vascular endothelial growth factor (VEGF) in the induction and control of vessel growth in the developing retina of rats and cais, using in situ hybridization techniques, VEGF is expressed successively in two layers of neural retina, the innermost (axon) layer and the inner nuclear layer (INL), In the axon layer, VEGF is expressed transiently by astrocytes as they spread across the layer, closely preceding the formation of superficial vessels, In the INL, VEGF is expressed transiently by somas at the middle of the layer (presumably Muller cells), closely preceding the formation of the deep layer of retinal vessels.We propose that hypoxia caused by the onset of neuronal activity is detected by strategically located populations of neuroglia, first astrocytes, then Muller cells, In response they secrete VEGF, inducing formation of the superficial and deep layers of retinal vessels, respectively, As the vessels become patent, they relieve the hypoxic stimulus, so vessel formation is matched to oxygen demand. This hypothesis was tested experimentally in three ways, Expression of the high affinity flk-1 receptor for VEGF was demonstrated in newly formed retinal vessels, confirming that the secreted VEGF acts on the vessels, in a paracrine fashion, Direct hypoxic regulation of VEGF expression by macroglia was demonstrated in primary cultures of astrocytes and in cells of a glioma line, Hypoxic regulation of VEGF expression in the intact developing retina was demonstrated by showing that oxygen-enriched atmospheres that inhibit vessel formation also suppress endogenous VEGF production.