Hosford Gayle E, Olson David M
Department of Physiology, Canadian Institutes of Health Research Group in Perinatal Health and Disease, The Perinatal Research Centre, The University of Alberta, Edmonton, Alberta, Canada T6G 2S2.
Am J Physiol Lung Cell Mol Physiol. 2003 Jul;285(1):L161-8. doi: 10.1152/ajplung.00285.2002. Epub 2003 Mar 7.
Signaling through the hypoxia inducible factor (HIF)-VEGF-VEGF receptor system (VEGF signaling system) leads to angiogenesis and epithelial cell proliferation and is a key mechanism regulating alveolarization in lungs of newborn rats. Hyperoxia exposure (>95% O2 days 4-14) arrests lung alveolarization and may do so through suppression of the VEGF signaling system. Lung tissue mRNA levels of HIF-2alpha and VEGF increased from days 4-14 in normoxic animals, but hyperoxia suppressed these increases. Levels of HIF-2alpha and VEGF mRNA were correlated in the air but not the O2-treated group, suggesting that the low levels of HIF-2alpha observed at high O2 concentrations are not stimulating VEGF expression. VEGF164 protein levels increased with developmental age, and with hyperoxia to day 9, but continuing hyperoxia decreased levels by day 12. VEGFR1 and VEGFR2 mRNA expression also increased in air-exposed animals, and these, too, were significantly decreased by hyperoxia by day 9 and day 12, respectively. Receptor protein levels did not increase with development; however, O2 did decrease protein to less than air values. Hyperoxic suppression of VEGF signaling from days 9-14 may be one mechanism by which alveolarization is arrested.
通过缺氧诱导因子（HIF）-血管内皮生长因子（VEGF）-VEGF受体系统（VEGF信号系统）进行的信号传导可导致血管生成和上皮细胞增殖，是调节新生大鼠肺中肺泡化的关键机制。暴露于高氧环境（第4 - 14天氧气浓度>95%）会阻止肺肺泡化，可能是通过抑制VEGF信号系统来实现的。在常氧动物中，HIF-2α和VEGF的肺组织mRNA水平在第4 - 14天有所增加，但高氧抑制了这些增加。在空气组而非氧气处理组中，HIF-2α和VEGF mRNA水平呈相关关系，这表明在高氧浓度下观察到的低水平HIF-2α并未刺激VEGF表达。VEGF164蛋白水平随发育年龄增加，在高氧环境下到第9天也是如此，但持续高氧到第12天则使其水平降低。在暴露于空气的动物中，VEGFR1和VEGFR2 mRNA表达也增加，并且这些表达在第9天和第12天分别也被高氧显著降低。受体蛋白水平并未随发育而增加；然而，高氧确实使蛋白水平降低至低于空气组的值。第9 - 14天高氧对VEGF信号的抑制可能是肺泡化被阻止的一种机制。
