Transgenic rabbits with increased VEGF expression develop hemangiomas in the liver: a new model for Kasabach-Merritt syndrome
Transgenic rabbits with increased VEGF expression develop hemangiomas in the liver: a new model for Kasabach-Merritt syndrome
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DOI：
10.1038/labinvest.3700346
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发表时间：
2005-12-01
影响因子：
5
通讯作者：
Fan, JL
中科院分区：
文献类型：
--
作者：
Kitajima, S;Liu, EQ;Fan, JL
临床研究提供了充足的证据，表明高水平（全身或局部）血管内皮生长因子（VEGF）与包括血管瘤在内的多种病理生理性疾病有关。为了研究 VEGF 表达升高是否会直接影响这些疾病，我们创建了转基因 (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) 转基因的肝脏表达增加。 Tg兔表现出明显的肝脏肿大，肝脏比对照兔重2.5倍。组织学分析显示，Tg兔的肝脏显示血窦显着扩张，并形成各种大小的血管网络，这是弥漫性血管瘤的特征。免疫组织化学染色显示肝细胞产生 VEGF165，而血浆中未检测到 VEGF165。此外，Tg兔出现溶血性贫血、血小板减少和脾肿大，这与明显的髓外造血有关。 Tg兔的表现模仿了人类血管瘤疾病的许多特征，例如卡萨巴赫-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的研究具有潜在的用途。
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 VEGF165, whereas plasma VEGF165 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.