Hepatocellular hypoxia-induced vascular endothelial growth factor expression and angiogenesis in experimental biliary cirrhosis
Hepatocellular hypoxia-induced vascular endothelial growth factor expression and angiogenesis in experimental biliary cirrhosis
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DOI：
10.1016/s0002-9440(10)65209-1
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发表时间：
1999-10-01
影响因子：
6
通讯作者：
Poupon, R
中科院分区：
文献类型：
--
作者：
Rosmorduc, O;Wendum, D;Poupon, R
我们测试了血管内皮生长因子（VEGF）和成纤维细胞生长因子-2（FGF-2）在与Sprague-Dawley大鼠胆总管结扎诱导的实验性肝纤维化相关的血管生成中的潜在作用。在正常大鼠中，VEGF和FGF-2的免疫反应仅限于不到3%的肝细胞。胆管结扎后一周，通过免疫检测整个小叶不均匀分布的哌莫硝唑加合物证明缺氧。2周后，缺氧和VEGF表达在>95%的肝细胞中检测到，并与门静脉周围血管内皮细胞增殖的增加共存，如通过Ki 67免疫标记所确定的。随后，在3周时，纤维化区域中的vonWillebrand标记的血管切片的密度显著增加。半定量逆转录聚合酶链反应显示，VEGF（120）和VEGF（164）的转录，对应于分泌亚型，增加在2周内，而VEGF（188）的转录保持不变。FGF-2主要由一个22 kd的亚型，根据蛋白质印迹，通过免疫组化确定在49%和100%的肝细胞在3周和7周，分别。我们的数据提供的证据表明，在胆汁型肝纤维化，血管生成刺激主要是由VEGF在肝细胞缺氧，而FGF-2可能有助于维持血管生成在后期阶段。
We tested the potential role of vascular endothelial growth factor (VEGF) and of fibroblast growth factor-2 (FGF-2) in the angiogenesis associated with experimental Liver fibrogenesis induced by common bile duct ligation in Sprague-Dawley rats. In normal rats, VEGF and FGF-2 immunoreactivities were restricted to less than 3% of hepatocytes, One week after bile duct ligation, hypoxia was demonstrated by the immunodetection of pimonidazole adducts unevenly distributed throughout the lobule. After 2 weeks, hypoxia and VEGF expression were detected in >95% of hepatocytes and coexisted with an increase in periportal vascular endothelial cell proliferation, as ascertained by Ki67 immunolabeling. Subsequently, at 3 weeks the density of von Willebrand-labeled vascular section in frbrotic areas significantly increased. Semiquantitative reverse transcription polymerase chain reaction showed that VEGF(120) and VEGF(164) transcripts, that correspond to secreted isoforms, increased within 2 weeks, while VEGF(188) transcripts remained unchanged. FGF-2 mainly consisting of a 22-kd isoform, according to Western blot, was identified by immunohistochemistry in 49% and 100% of hepatocytes at 3 and 7 weeks, respectively. Our data provide evidence that in biliary-type liver fibrogenesis, angiogenesis is stimulated primarily by VEGF in response to hepatocellular hypoxia while FGF-2 likely contributes to the maintenance of angiogenesis at later stages.