Regulation of vascular endothelial growth factor by oxygen in a model of retinopathy of prematurity
Regulation of vascular endothelial growth factor by oxygen in a model of retinopathy of prematurity
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DOI：
10.1001/archopht.1996.01100140419009
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发表时间：
1996-10-01
影响因子：
--
通讯作者：
Smith, LEH
中科院分区：
文献类型：
--
作者：
Pierce, EA;Foley, ED;Smith, LEH
目的：探讨血管内皮生长因子(VEGF)在早产儿视网膜病变(ROP)第一期发病机制中的作用及补充氧疗抑制ROP第二期新生血管形成的机制。方法：采用荧光素-葡聚糖灌流与全视网膜原位杂交相结合的方法，检测高氧暴露新生小鼠视网膜中血管定位与血管表达的关系。Northern印迹和免疫印迹分析定量分析高氧引起的血管内皮生长因子信使RNA和蛋白表达的变化。结果：在生后7d，正常视网膜中血管内皮生长因子信使RNA在发育中的血管前方以网状结构的形式产生。高氧可使周边视网膜中血管内皮生长因子的表达下调，同时伴有生长停滞和部分发育中的血管的丧失。在75%氧气中孵育6小时后，生后7天动物视网膜中总的血管内皮生长因子信使RNA和蛋白水平分别下降了55%和85%。外源性血管内皮细胞生长因子可抑制57%的瓶闭塞。在继发于血管丧失的视网膜缺血的动物中，补充氧疗使刺激的视网膜血管内皮生长因子水平降低约70%。结论：高氧下调血管内皮生长因子的表达可能是导致ROP发生的早产儿血管闭塞和正常视网膜血管生长停止的部分原因。高氧还有可能用于治疗，下调低氧视网膜中血管内皮生长因子的表达，以期限制ROP的新生血管并发症。基于这些关于视网膜血管内皮生长因子表达调控的发现，我们对ROP的发病机制提出了解释。
Objectives: To investigate the role of vascular endothelial growth factor (VEGF) in the pathogenesis of the first phase of retinopathy of prematurity (ROP) and to examine the mechanism by which supplemental oxygen therapy might inhibit neovascularization in the second phase of ROP.Methods: A novel combination of fluorescein-dextran perfusion and colorimetric whole-retina in situ hybridization was used to evaluate the expression of VEGF messenger RNA in relationship to the location of blood vessels in retinas from neonatal mice that were exposed to hyperoxia. Northern blot and immunoblot analyses were used to quantify the changes in VEGF messenger RNA and protein expression caused by hyperoxia. The ability of VEGF to prevent hyperoxia-induced vaso-obliteration was evaluated by injecting exogenous VEGF into the vitreous cavity prior to oxygen exposure.Results: Vascular endothelial growth factor messenger RNA was produced in a reticular pattern just anterior to the developing blood vessels in normal retina on postnatal day 7. The expression of VEGF in the peripheral retina was down-regulated by hyperoxia in conjunction with the arrest of growth and the loss of some of the developing vasculature. Total VEGF messenger RNA and protein levels in retinas from animals on postnatal day 7 were decreased 55% and 85%, respectively, after 6 hours in 75% oxygen. Vase-obliteration was inhibited 57% by pretreatment of animals with exogenous VEGF. In animals with retinal ischemia secondary to loss of vasculature, treatment with supplemental oxygen therapy decreased stimulated retinal VEGF levels by approximately 70%.Conclusions: Down-regulation of VEGF expression by hyperoxia may be partly responsible for the vaso-obliteration and cessation of normal retinal blood vessel growth observed in premature infants in whom ROP develops. Hyperoxia also has the potential to be used therapeutically to down-regulate VEGF expression in hypoxic retina in the hope of limiting the neovascular complications of ROP. Based on these findings about the regulation of VEGF expression in the retina, an explanation of the pathogenesis of ROP is proposed.