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Blood, 9 July 2009, Vol. 114, No. 2, pp. 469-477.
Prepublished online as a Blood First Edition Paper on May 13, 2009; DOI 10.1182/blood-2008-12-193581.
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VASCULAR BIOLOGY
Endothelial deletion of hypoxia-inducible factor–2 (HIF-2) alters vascular function and tumor angiogenesis
Nicolas Skuli1,2,*,
Liping Liu1,2,*,
Anja Runge1,2,
Tao Wang3,
Lijun Yuan3,
Sunny Patel1,
Luisa Iruela-Arispe4,
M. Celeste Simon1,2,5, and
Brian Keith16
1 Abramson Family Cancer Research Institute,
2 Howard Hughes Medical Institute, and
3 Penn Cardiovascular Institute, University of Pennsylvania, Philadelphia;
4 Department of Molecular, Cell and Developmental Biology, University of California Los Angeles; and
Departments of 5 Cell and Developmental Biology and
6 Cancer Biology, University of Pennsylvania School of Medicine, Philadelphia
Hypoxia-inducible factor–2 (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 physiologic 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 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-2 in vascular endothelial cells.
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