Transgenic rabbits with increased VEGF expression develop hemangiomas in the liver: a new model for Kasabach-Merritt syndrome.
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.
Kitajima
Shuji
S
Analytical Research Center for Experimental Sciences, Saga University, Saga, Japan.
Liu
Enqi
E
Morimoto
Masatoshi
M
Koike
Tomonari
T
Yu
Ying
Y
Watanabe
Teruo
T
Imagawa
Shigehiko
S
Fan
Jianglin
J
D000743:Anemia, Hemolytic / Q000235:genetics / Q000473:pathology; D000818:Animals; D030801:Animals, Genetically Modified; D015152:Blotting, Northern; D004195:Disease Models, Animal; D004912:Erythrocytes / Q000648:ultrastructure; D005260:Female; D015870:Gene Expression; D006391:Hemangioma / Q000235:genetics* / Q000473:pathology; D006403:Hematologic Tests; D006411:Hematopoiesis, Extramedullary / Q000235:genetics; D022781:Hepatocytes / Q000378:metabolism / Q000473:pathology; D006801:Humans; D008113:Liver Neoplasms / Q000235:genetics* / Q000473:pathology; D008297:Male; D012333:RNA, Messenger / Q000378:metabolism; D011817:Rabbits; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013163:Splenomegaly / Q000235:genetics / Q000473:pathology; D013577:Syndrome; D013921:Thrombocytopenia / Q000235:genetics / Q000473:pathology; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics*
D012333:RNA, Messenger; C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A