Kremer C, Breier G, Risau W, Plate K H
Department of Neuropathology, Neurocenter, Freiburg University Medical School, Germany.
Cancer Res. 1997 Sep 1;57(17):3852-9.
Vascular endothelial growth factor (VEGF) and its tyrosine kinase receptors VEGFR-1 (flt-1) and VEGFR-2 (flk-1/KDR) are key mediators of physiological and pathological angiogenesis. They are expressed in most tissues during embryonic development but are down-regulated in the adult, when angiogenesis ceases. Up-regulation of VEGFR-2 and of VEGF are observed in many pathological conditions under which angiogenesis is reinduced. A major regulator of VEGF expression is hypoxia. Although the temporal expression pattern of VEGFR-2 parallels VEGF expression to a high extent, little is known about its regulation. Here, we show that VEGFR-2 is highly expressed in early postnatal mouse brain but is down-regulated commencing at postnatal day 15 (P15) of mouse brain development and is hardly detectable in P30 mouse brain. Using P30 mouse brain slices, we observed that hypoxia up-regulates VEGFR-2 in the slices but not in human umbilical vein endothelial cells, suggesting the presence of a hypoxia-inducible factor in the murine neuroectoderm that up-regulates VEGFR-2. To identify the factors involved, normoxic P30 cerebral slices were cultured with growth factors that are either hypoxia-inducible (e.g., PDGF-BB, erythropoietin, and VEGF) and/or are known to act on endothelial cells (e.g., PDGF-BB, VEGF, and PIGF). Exogenously added recombinant VEGF led to an up-regulation of VEGFR-2 expression, which could be inhibited by preincubation with a neutralizing anti-VEGF antibody. Addition of PDGF-BB, PIGF, and erythropoietin had no effect on VEGFR-2 expression. Our results suggest a differential but synergistic regulation by hypoxia of VEGF and VEGFR-2: a direct induction of VEGF that subsequently up-regulates VEGFR-2 in endothelial cells. This autoenhancing system may represent an important mechanism of tumor angiogenesis.
血管内皮生长因子（VEGF）及其酪氨酸激酶受体VEGFR-1（flt-1）和VEGFR-2（flk-1/KDR）是生理和病理血管生成的关键介质。它们在胚胎发育期间在大多数组织中表达，但在成年期血管生成停止时被下调。在许多重新诱导血管生成的病理条件下，可观察到VEGFR-2和VEGF的上调。VEGF表达的一个主要调节因子是缺氧。尽管VEGFR-2的时间表达模式在很大程度上与VEGF表达平行，但其调节机制却知之甚少。在这里，我们表明VEGFR-2在出生后早期的小鼠大脑中高度表达，但在小鼠大脑发育的出生后第15天（P15）开始下调，在P30小鼠大脑中几乎检测不到。使用P30小鼠脑片，我们观察到缺氧可上调脑片中的VEGFR-2，但在人脐静脉内皮细胞中则不然，这表明在鼠神经外胚层中存在一种缺氧诱导因子可上调VEGFR-2。为了确定其中涉及的因素，将常氧P30脑片与缺氧诱导的生长因子（如血小板衍生生长因子BB（PDGF-BB）、促红细胞生成素和VEGF）和/或已知作用于内皮细胞的生长因子（如PDGF-BB、VEGF和胎盘生长因子（PIGF））一起培养。外源添加的重组VEGF导致VEGFR-2表达上调，而用中和抗VEGF抗体预孵育可抑制这种上调。添加PDGF-BB、PIGF和促红细胞生成素对VEGFR-2表达没有影响。我们的结果表明缺氧对VEGF和VEGFR-2有差异但协同的调节作用：直接诱导VEGF，随后在内皮细胞中上调VEGFR-2。这种自我增强系统可能代表肿瘤血管生成的一个重要机制。
