1. ¹Analytical Research Center for Experimental Sciences, Saga University, Saga, Japan
2. ²Cardiovascular Disease Laboratory, Department of Pathology, Institute of Basic Medical Sciences, University of Tsukuba, Tsukuba, Japan
3. ³President's Office, Saga University, Saga, Japan
4. ⁴Division of Hematology, Institute of Clinical Medicine, University of Tsukuba, Tsukuba, Japan

Correspondence: Dr J Fan, MD, PhD, Cardiovascular Disease Laboratory, Department of Pathology, Institute of Basic Medical Sciences, University of Tsukuba, Tsukuba 305-8575, Japan. E-mail: J-LFAN@md.tsukuba.ac.jp

Received 17 April 2005; Revised 3 August 2005; Accepted 4 August 2005; Published online 3 October 2005.

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 VEGF₁₆₅ transgene under the control of the human -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.