Transgenic rabbits with increased VEGF expression develop hemangiomas in the liver: a new model for Kasabach–Merritt syndrome

Abstract

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 a-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.

Increased Expression of Vascular Endothelial Growth Factor in Kidney Leads to Progressive Impairment of Glomerular Functions

“…Ultrathin sections were doubly stained with uranyl acetate and lead citrate and were observed under an JEM-100CX electron microscope (JEOL Ltd, Tokyo, Japan) as described previously. 32 …”

“…32 A previous study showed that the ␣-1-antitrypsin promoter contained an element that was able to direct the expression of the transgene in the kidney in addition to the liver. 13 Three founders were obtained, but one founder died before breeding.…”

Comparison of Glycerol, Lactamide, Acetamide and Dimethylsulfoxide as Cryoprotectants of Japanese White Rabbit Spermatozoa

“…52: [511][512][513][514][515][516] 2006) he rabbit is considered to be a valuable laboratory animal for research in teratology, immunology, microbiology, and medical and life sciences. In addition, many valuable mutants [1,2] including transgenic [3][4][5][6], have been established in the rabbit. Therefore, a need has been recognized for reliable methods to bank rabbit genetic resources efficiently in the form of cryopreserved spermatozoa.…”

Overexpression of Notch1 Ectodomain in Myeloid Cells Induces Vascular Malformations through a Paracrine Pathway

“…This is consistent with the decreased vascular branching in CD4C/N1 EC Tg liver, in contrast with the enhanced angiogenesis that would be expected if vascular endothelial growth factor levels were elevated. 61 Moreover, Tg rabbits overexpressing vascular endothelial growth factor in the liver under the regulation of the human ␣-antitrypsin promoter develop vascular malformations 62 but no superficial large vessels, as observed in CD4C/N1 EC Tg mice. Our search, however, revealed interesting candidates (MCP-1, MCP-5, FIII, FXIII-A, Jag1, and Egr-1) already known to be implicated in angiogenesis.…”