Minchenko A, Bauer T, Salceda S, Caro J
Department of Medicine, Cardeza Foundation for Hematologic Research, Jefferson Medical College of Thomas Jefferson University, Philadelphia, Pennsylvania.
Lab Invest. 1994 Sep;71(3):374-9.
Vascular endothelial growth factor (VEGF) is a specific endothelial cell mitogen with potent angiogenic properties. In tumors, VEGF has been localized to the most necrotic and ischemic areas of the tissues, suggesting that local hypoxia is a potent inducer of VEGF production. Initial experiments in vitro confirmed the stimulatory effect of hypoxia on VEGF expression. The extent of this response and the mechanisms involved in oxygen sensing are poorly characterized.
Confluent monolayers of malignant cell lines or primary cultures of fibroblast or endothelial cells were exposed to hypoxia or incubated with either cobalt chloride, a stimulator of erythropoietin gene expression, or sodium azide, an inhibitor of oxydative phosphorylation. VEGF expression was analyzed by Northern blot or RNase protection assays. The expression VEGF in vivo was studied in animals subjected to hypobaric hypoxia or functional anemia.
Hypoxia greatly stimulated VEGF expression in tumor cell lines and primary fibroblast cultures. Endothelial cells, that expressed very low constitutive levels of VEGF, were resistant to hypoxic stimulation. RNase protection analysis showed that hypoxia primarily stimulated the induction of smaller and medium VEGF isoforms, i.e., the same ones expressed under normal conditions. The stimulatory effect of hypoxia on VEGF could be reproduced in vitro by cobalt chloride but not with sodium azide. In vivo, both hypoxia and anemia were found to be potent inducers of VEGF expression in several organs including heart, brain, liver, kidney, and muscle. As in vitro, cobalt was also found to be a potent stimulator of VEGF in vivo.
Hypoxia is a potent inducer of VEGF expression in malignant as well as normal cultured cells. It is also a stimulator of VEGF expression in vivo. The VEGF gene appears to respond to hypoxia like the erythropoietin gene, and the mechanism of oxygen sensing probably is mediated by a heme-containing protein.
血管内皮生长因子（VEGF）是一种具有强大血管生成特性的特异性内皮细胞促分裂原。在肿瘤中，VEGF定位于组织中最坏死和缺血的区域，这表明局部缺氧是VEGF产生的有力诱导因素。最初的体外实验证实了缺氧对VEGF表达的刺激作用。这种反应的程度以及氧感应所涉及的机制尚不清楚。
将恶性细胞系的汇合单层细胞或成纤维细胞或内皮细胞的原代培养物暴露于缺氧环境，或与促红细胞生成素基因表达的刺激剂氯化钴或氧化磷酸化抑制剂叠氮化钠一起孵育。通过Northern印迹或核糖核酸酶保护试验分析VEGF表达。在经受低压缺氧或功能性贫血的动物中研究体内VEGF的表达。
缺氧极大地刺激了肿瘤细胞系和成纤维细胞原代培养物中VEGF的表达。内皮细胞VEGF的组成型表达水平很低，对缺氧刺激有抗性。核糖核酸酶保护分析表明缺氧主要刺激较小和中等VEGF异构体的诱导，即正常条件下表达的那些异构体。缺氧对VEGF的刺激作用在体外可由氯化钴重现，但不能由叠氮化钠重现。在体内，发现缺氧和贫血都是包括心脏、脑、肝、肾和肌肉在内的多个器官中VEGF表达的有力诱导因素。与体外情况一样，钴在体内也是VEGF的有力刺激剂。
缺氧是恶性及正常培养细胞中VEGF表达的有力诱导因素。它也是体内VEGF表达的刺激因素。VEGF基因似乎像促红细胞生成素基因一样对缺氧作出反应，氧感应机制可能由一种含血红素的蛋白质介导。
