Endothelial deletion of hypoxia-inducible factor-2alpha (HIF-2alpha) alters vascular function and tumor angiogenesis.
Hypoxia-inducible factor-2alpha (HIF-2alpha) is highly expressed in embryonic vascular endothelial cells (ECs) and activates the expression of target genes whose products modulate vascular function and angiogenesis. In this report, we describe a genetic model designed to test the physiologic consequences of deleting HIF-2alpha in murine endothelial cells. Surprisingly, mice with HIF-2alpha-deficient ECs developed normally but displayed a variety of phenotypes, including increased vessel permeability, aberrant endothelial cell ultrastructure, and pulmonary hypertension. Moreover, these animals exhibited defective tumor angiogenesis associated with increased hypoxic stress and tumor cell apoptosis. Immortalized HIF-2alpha-deficient ECs displayed decreased adhesion to extracellular matrix proteins and expressed reduced levels of transcripts encoding fibronectin, integrins, endothelin B receptor, angiopoietin 2, and delta-like ligand 4 (Dll4). Together, these data identify unique cell-autonomous functions for HIF-2alpha in vascular endothelial cells.
Skuli
Nicolas
N
Abramson Family Cancer Research Institute, University of Pennsylvania, Philadelphia, PA 19104-6160, USA.
Liu
Liping
L
Runge
Anja
A
Wang
Tao
T
Yuan
Lijun
L
Patel
Sunny
S
Iruela-Arispe
Luisa
L
Simon
M Celeste
MC
Keith
Brian
B
D000483:Alleles; D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D045744:Cell Line, Tumor; D004622:Embryo, Mammalian / Q000196:embryology / Q000378:metabolism; D042783:Endothelial Cells / Q000378:metabolism*; D015972:Gene Expression Regulation, Neoplastic; D006976:Hypertension, Pulmonary / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology; D000860:Hypoxia / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D008854:Microscopy, Electron; D009369:Neoplasms / Q000098:blood supply* / Q000235:genetics / Q000378:metabolism*; D009389:Neovascularization, Pathologic; D023041:Xenograft Model Antitumor Assays; D000099162:Endothelial PAS Domain-Containing Protein 1
D051792:Basic Helix-Loop-Helix Proteins; D000099162:Endothelial PAS Domain-Containing Protein 1