Submitted December 9, 2008
Accepted April 28, 2009
Endothelial deletion of hypoxia inducible factor-2alpha (HIF-2
) alters vascular function and tumor angiogenesis
Nicolas Skuli, Liping Liu, Anja Runge, Tao Wang, Lijun Yuan, Sunny Patel, Luisa Iruela-Arispe, M. Celeste Simon*, and Brian Keith
Abramson Family Cancer Research Institute, University of Pennsylvania, Philadelphia, PA, United States
Howard Hughes Medical Institute, University of Pennsylvania, Philadelphia, PA, United States
Penn Cardiovascular Institute, University of Pennsylvania, Philadelphia, PA, United States
Department of Molecular, Cell and Developmental Biology, University of California Los Angeles, Los Angeles, CA, United States
Department of Cell and Developmental Biology, University of Pennsylvania School of Medicine, Philadelphia, PA, United States
Department of Cancer Biology, University of Pennsylvania School of Medicine, Philadelphia, PA, United States
* Corresponding author; email: celeste2{at}mail.med.upenn.edu.
Hypoxia inducible factor-2alpha (HIF-2
) 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 physiological consequences of deleting HIF-2 in murine endothelial cells. Surprisingly, mice with HIF-2 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-2 deficient ECs displayed decreased adhesion to extra-cellular matrix proteins and expressed reduced levels of transcripts encoding fibronectin, integrins, endothelin B receptor (ET-B), angiopoietin 2 (Ang2) and delta-like ligand 4 (Dll4). Together, these data identify unique cell-autonomous functions for HIF-2 in vascular endothelial cells.
