1. ¹Department of Medicine, University of Pennsylvania School of Medicine, Philadelphia, PA, USA
2. ²Division of Biological Sciences, University of California-San Diego, La Jolla, CA, USA
3. ³Abramson Family Cancer Research Institute and Howard Hughes Medical Institute, University of Pennsylvania School of Medicine, Philadelphia, PA, USA

Correspondence: Dr VH Haase, Department of Medicine, University of Pennsylvania School of Medicine, 626 Clinical Research Building, 415 Curie Boulevard, Philadelphia, PA 19104-6144, USA. E-mail: vhaase@mail.med.upenn.edu

Received 8 November 2007; Revised 17 March 2008; Accepted 8 April 2008; Published online 19 May 2008.

Abstract

The von Hippel–Lindau tumor suppressor pVHL regulates the stability of hypoxia-inducible factors (HIF)-1 and -2, oxygen-sensitive basic helix–loop–helix transcription factors, which mediate the hypoxic induction of angiogenic growth factors such as vascular endothelial growth factor. Loss of pVHL function results in constitutive activation of HIF-1 and HIF-2 and is associated with the development of highly vascularized tumors in multiple organs. We have used a conditional gene-targeting approach to investigate the relative contributions of HIF-1 and HIF-2 to VHL-associated vascular tumorigenesis in a mouse model of liver hemangiomas. Here we demonstrate genetically that conditional inactivation of HIF-2 suppressed the development of VHL-associated liver hemangiomas and that angiogenic gene expression in hepatocytes is predominantly regulated by HIF-2 and not by HIF-1. These findings suggest that HIF-2 is the dominant HIF in the pathogenesis of VHL-associated vascular tumors and that pharmacologic targeting of HIF-2 may be an effective strategy for their treatment.