TY - JOUR
T1 - Endothelial deletion of hypoxia-inducible factor-2α (HIF-2α) alters vascular function and tumor angiogenesis
AU - Skuli, Nicolas
AU - Liu, Liping
AU - Runge, Anja
AU - Wang, Tao
AU - Yuan, Lijun
AU - Patel, Sunny
AU - Iruela-Arispe, Luisa
AU - Simon, M. Celeste
AU - Keith, Brian
PY - 2009
Y1 - 2009
N2 - Hypoxia-inducible factor-2α (HIF-2α) 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-2α in murine endothelial cells. Surprisingly, mice with HIF-2α-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-2α-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-2α in vascular endothelial cells.
AB - Hypoxia-inducible factor-2α (HIF-2α) 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-2α in murine endothelial cells. Surprisingly, mice with HIF-2α-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-2α-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-2α in vascular endothelial cells.
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U2 - 10.1182/blood-2008-12-193581
DO - 10.1182/blood-2008-12-193581
M3 - Article
C2 - 19439736
AN - SCOPUS:67651098992
SN - 0006-4971
VL - 114
SP - 469
EP - 477
JO - Blood
JF - Blood
IS - 2
ER -