Kitajima Shuji, Liu Enqi, Morimoto Masatoshi, Koike Tomonari, Yu Ying, Watanabe Teruo, Imagawa Shigehiko, Fan Jianglin
Analytical Research Center for Experimental Sciences, Saga University, Saga, Japan.
Lab Invest. 2005 Dec;85(12):1517-27. doi: 10.1038/labinvest.3700346.
Clinical studies have provided ample evidence that high (either systemic or local) levels of vascular endothelial growth factor (VEGF) are associated with several pathophysiological disorders, including hemangiomas. To investigate whether elevated VEGF expression could directly affect these disorders, we created a transgenic (Tg) rabbit model with increased hepatic expression of the human VEGF(165) transgene under the control of the human alpha-antitrypsin promoter. Tg rabbits exhibited marked hepatomegaly, with livers 2.5-fold heavier than those of control rabbits. Histological analysis revealed that the livers of Tg rabbits showed prominent dilation of the sinusoids and formed various-sized blood vessel networks, a feature of diffuse hemangiomas. Immunohistochemical staining revealed that the hepatocytes produced VEGF(165), whereas plasma VEGF(165) was not detected. Furthermore, Tg rabbits suffered from hemolytic anemia, thrombocytopenia and splenomegaly, which was associated with marked extramedullary hematopoiesis. The manifestations of Tg rabbits mimic many of the features of hemangiomatous disorders in humans such as the Kasabach-Merritt syndrome, and therefore this model may be potentially useful for the study of the pathogenesis and complications of hemangiomas as well as the investigation of angiogenesis inhibitors.
临床研究已提供充分证据表明，高（全身或局部）水平的血管内皮生长因子（VEGF）与多种病理生理紊乱相关，包括血管瘤。为了研究VEGF表达升高是否会直接影响这些紊乱，我们构建了一种转基因（Tg）兔模型，该模型在人α-抗胰蛋白酶启动子的控制下，人VEGF(165)转基因在肝脏中的表达增加。Tg兔表现出明显的肝肿大，其肝脏重量比对照兔的肝脏重2.5倍。组织学分析显示，Tg兔的肝脏呈现出肝血窦显著扩张并形成各种大小的血管网络，这是弥漫性血管瘤的一个特征。免疫组织化学染色显示肝细胞产生VEGF(165)，而血浆中未检测到VEGF(165)。此外，Tg兔患有溶血性贫血、血小板减少症和脾肿大，这与明显的髓外造血有关。Tg兔的表现模拟了人类血管瘤性疾病的许多特征，如卡萨巴赫-梅里特综合征，因此该模型可能对研究血管瘤的发病机制和并发症以及血管生成抑制剂具有潜在的用途。
