Department of Surgery, Hyogo College of Medicine, Nishinomiya, Japan.
Surgery. 2013 Jan;153(1):70-7. doi: 10.1016/j.surg.2012.06.021. Epub 2012 Aug 3.
Recent studies of hepatic regeneration have mainly focused on the growth of parenchymal cells. However, remodeling of liver vessels seems to be crucial during hepatic regeneration. In this study, we investigated the influence of antiangiogenesis on hepatic regeneration using sFlt-1, a soluble receptor for vascular endothelial growth factor that acts as a dominant negative receptor, and the hepatocyte growth factor antagonist NK4.
A sFlt-1-expressing adenoviral vector, an NK4-expressing adenoviral vector, or both combined were infected into C57BL6 mice via the tail vein. A 70% partial hepatectomy was performed on all of the mice 48 hours after infection. The remnants of the liver were removed after the partial hepatectomy, and hepatic regeneration was assessed by measuring the remnant liver weight and hepatocyte mitosis, bromodeoxyuridine staining, immunohistochemical staining with anti-platelet endothelial cell adhesion molecule-1 antibodies, and real-time polymerase chain reaction studies for angiogenic factors.
The immunohistochemical staining for CD31 showed suppression of sinusoidal endothelial cells growth in sFlt-1-expressing adenoviral vector-and NK4-expressing adenoviral vector-infected mice. Increases in the remnant hepatic weight were significantly lower in the sFlt-1-expressing adenoviral vector-infected mice. The bromodeoxyuridine index and mitotic cell results revealed a significant decrease in hepatic regeneration in the sFlt-1-expressing adenoviral vector-and NK4-expressing adenoviral vector-infected mice. The suppressive effects on hepatic regeneration were significantly enhanced by combined sFlt-1-expressing adenoviral vector and NK4-expressing adenoviral vector infection. Real-time polymerase chain reaction results revealed the significant suppression of angiogenic growth factor receptors Tie-1 and Tie-2.
The angiogenesis inhibitor significantly suppressed hepatic regeneration. These results suggest that hepatic regeneration after hepatectomy closely correlates with angiogenesis.
最近的肝再生研究主要集中在实质细胞的生长上。然而，肝血管的重构似乎在肝再生过程中至关重要。在这项研究中，我们使用可溶性血管内皮生长因子受体 sFlt-1（一种作为显性负受体的血管内皮生长因子的可溶性受体）和肝细胞生长因子拮抗剂 NK4 来研究抗血管生成对肝再生的影响。
通过尾静脉将表达 sFlt-1 的腺病毒载体、表达 NK4 的腺病毒载体或两者的组合感染到 C57BL6 小鼠中。在感染后 48 小时对所有小鼠进行 70%部分肝切除术。在部分肝切除术后取出剩余的肝脏，并通过测量剩余肝重和肝细胞有丝分裂、溴脱氧尿苷染色、抗血小板内皮细胞黏附分子-1 抗体的免疫组织化学染色以及血管生成因子的实时聚合酶链反应研究来评估肝再生。
CD31 的免疫组织化学染色显示，在表达 sFlt-1 的腺病毒载体和表达 NK4 的腺病毒载体感染的小鼠中，窦内皮细胞的生长受到抑制。表达 sFlt-1 的腺病毒载体感染的小鼠的剩余肝重增加明显较低。溴脱氧尿苷指数和有丝分裂细胞结果显示，在表达 sFlt-1 的腺病毒载体和表达 NK4 的腺病毒载体感染的小鼠中，肝再生明显减少。表达 sFlt-1 的腺病毒载体和表达 NK4 的腺病毒载体联合感染可显著增强对肝再生的抑制作用。实时聚合酶链反应结果显示，血管生成生长因子受体 Tie-1 和 Tie-2 的表达受到显著抑制。
血管生成抑制剂显著抑制肝再生。这些结果表明，肝切除术后的肝再生与血管生成密切相关。
