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Analysis of the role of angiogenesis and non-parenchymal cells during hepatic regeneration.

分析血管生成和非实质细胞在肝再生过程中的作用。

基本信息

批准号：
17390375
负责人：
FUJIMOTO Jiro
金额：
$ 9.54万
依托单位：
Hyogo College of Medicine
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (B)
财政年份：
2005
资助国家：
日本
起止时间：
2005 至 2006
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-17390375/
关键词：
angiogenesis HGF NK4 VEGF sFlt-1 liver regeneration NK4

项目摘要

We investigated the influence of anti-angiogenesis for hepatic regeneration using HGF antagonist (NK4) and suppressor of VEGF receptor (sFlt-1). NK4 expressing adenoviral vector (Ad.NK4) or sFlt-1 expressing adenoviral vector (Ad.sFlt-1) were infected mice liver. Seventy percent hepatectomy was performed 48 hours after infection. LacZ expressing adenoviral vector (Ad.LacZ) was used as control. Expression of Nk4 or sFlt-1 reached maximum level 48 hours after infection (NK4: 300ng/ml, sFlt-1:350ng/ml) and sustained for 2 weeks. Remnant liver was removed at 12, 24, 36, 48, 72 and 120 hrs after partial hepatectomy, and hepatic regeneration was assessed. As a result, increase of remnant hepatic weight was significantly delayed in Ad.NK4 or Ad.sFlt-1 infected mice. Results of mitotic cells and BrdU index showed significant delay of hepatic regeneration in Ad.NK4 or Ad.sFlt-1 infected mice at 48 or 36 hours after hepatectomy. Immnuhistochemical staining of CD31 showed suppression of sinusoidal endothelial cells growth in Ad.NK4 infected mice. Ang-1, Ang-2, Tie-1, and Tie-2 are considered to be crucial in the process of maturation of vessels. Real time PCR showed suppression of mRNA of Ang-1, Ang-2, Tie-1, and Tie-2 with significant difference. These results suggested that hepatic regeneration after hepatectomy closely correlates with angiogenesis.

我们研究了使用 HGF 拮抗剂 (NK4) 和 VEGF 受体抑制剂 (sFlt-1) 抗血管生成对肝再生的影响。表达NK4的腺病毒载体(Ad.NK4)或表达sFlt-1的腺病毒载体(Ad.sFlt-1)感染小鼠肝脏。感染后 48 小时进行了 70% 的肝切除术。使用表达LacZ的腺病毒载体(Ad.LacZ)作为对照。 Nk4或sFlt-1的表达在感染后48小时达到最高水平（NK4：300ng/ml，sFlt-1：350ng/ml）并持续2周。部分肝切除后12、24、36、48、72和120小时取出残余肝脏，并评估肝再生。结果，Ad.NK4或Ad.sFlt-1感染的小鼠中残余肝重量的增加显着延迟。有丝分裂细胞和BrdU指数的结果显示，Ad.NK4或Ad.sFlt-1感染的小鼠在肝切除术后48或36小时肝再生显着延迟。 CD31 的免疫组织化学染色显示 Ad.NK4 感染小鼠的窦内皮细胞生长受到抑制。 Ang-1、Ang-2、Tie-1 和 Tie-2 被认为在血管成熟过程中至关重要。实时PCR显示Ang-1、Ang-2、Tie-1和Tie-2的mRNA受到显着抑制。这些结果表明肝切除术后的肝再生与血管生成密切相关。