title: HIF in vascular development and tumour angiogenesis.
abstract: Hypoxia stimulates angiogenesis through the up-regulation of vascular endothelial growth factor and other angiogenic cytokines. Members of the hypoxia-inducible factor (HIF) family of transcription factors play a central role in the cellular hypoxia response. To address the function of HIF signalling in physiological and pathological angiogenesis, we used a dominant-negative approach that interferes with the function of both HIF-1 and HIF-2. The expression of a dominant-negative HIF mutant in endothelial cells inhibited endothelial sprouting and disrupted cardiovascular development in mouse embryos, demonstrating that endothelial HIF function is essential for embryogenesis. However, the inhibition of HIF activity in tumour vessels accelerated the growth of experimental fibrosarcoma and osteosarcoma. The over-expression of prolyl hydroxylase domain protein 2 (PHD2), an enzyme that negatively regulates HIF stability, strongly reduced growth of LM8 osteosarcoma cells in vivo. Our results are in line with the complexity of HIF function and indicate that HIF inhibition might not be an ideal anti-tumour strategy.
authors.affiliation: Division of Endothelial Cell Biology, Department of Pathology, University of Technology, Dresden, Germany.
authors.forename: Georg
authors.initials: G
authors.lastname: Breier
authors.forename: Alexander H
authors.initials: AH
authors.lastname: Licht
authors.forename: Anke
authors.initials: A
authors.lastname: Nicolaus
authors.forename: Anne
authors.initials: A
authors.lastname: Klotzsche
authors.forename: Ben
authors.initials: B
authors.lastname: Wielockx
authors.forename: Zuzana
authors.initials: Z
authors.lastname: Kirsnerova
mesh_terms: D000818:Animals; D001808:Blood Vessels / Q000196:embryology*; D002319:Cardiovascular System / Q000196:embryology; D042783:Endothelial Cells / Q000201:enzymology / Q000378:metabolism; D051793:Hypoxia-Inducible Factor 1 / Q000737:chemistry / Q000378:metabolism*; D051379:Mice; D009369:Neoplasms / Q000098:blood supply* / Q000378:metabolism*; D009389:Neovascularization, Pathologic / Q000378:metabolism* / Q000628:therapy; D040262:Receptors, Vascular Endothelial Growth Factor / Q000378:metabolism
chemical_list: D051793:Hypoxia-Inducible Factor 1; D040262:Receptors, Vascular Endothelial Growth Factor