The transcription factor EPAS-1/hypoxia-inducible factor 2α plays an important role in vascular remodeling

Peng, Jun; Zhang, Liyong; Drysdale, Linsay; Fong, Guo-Hua

doi:10.1073/pnas.140087397

Cited by 460Angiogenesis and VEGF in CancerDevelopmental Biology and Gene RegulationBarrier Structure and Function Studies

The transcription factor EPAS-1/hypoxia-inducible factor 2α plays an important role in vascular remodeling

Open access

Peng, Jun, Zhang, Liyong, Drysdale, Linsay, Fong, Guo-Hua·2000·Proceedings of the National Academy of Sciences

DOI 10.1073/pnas.140087397PMC PMC26957

Open this paper in CoChat — free account

Abstract

We have studied the role of the basic helix–loop–helix–PAS transcription factor EPAS-1/hypoxia-inducible factor 2α in vascular development by gene targeting. In ICR/129 Sv outbred background, more than half of the mutants displayed varying degrees of vascular disorganization, typically in the yolk sac, and died in utero between embryonic day (E)9.5 and E13.5. In mutant embryos directly derived from EPAS-1 −/− embryonic stem cells (hence in 129 Sv background), all embryos developed severe vascular defects both in the yolk sac and embryo proper and died between E9.5 and E12.5. Normal blood vessels were formed by vasculogenesis but they either fused improperly or failed to assemble into larger vessels later during development. Our results suggest that EPAS-1 plays an important role at postvasculogenesis stages and is required for the remodeling of the primary vascular network into a mature hierarchy pattern.

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

Integrity signals

Registry

Crossref · 10.1073/pnas.140087397

Cites

0 citation errors · 0 not checkable

Statistics

Claims the paper makes

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

Vascularization is severely impaired in HIF1A-/- and HIF2A-/- mice.
“Vascularization is severely impaired in HIF1A -/- (Carmeliet et al., 1998;Ryan et al., 1998) and HIF2A -/- (Peng et al., 2000) mice.”
From Therapeutic targeting of hypoxia and hypoxia-inducible factors in cancer (2016) · cites this paper as Peng et al., 2000

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

The self-check needs the paper’s full text.

Cellular and developmental control of O 2 homeostasis by hypoxia-inducible factor 1α
Iyer, N. V., Kotch, L. E., Agani, F., Leung, S. W., Laughner, E., Wenger, R. H., Gassmann, M., Gearhart, J. D., Lawler, A. M., Yu, A. Y., et al. (1998) · Genes & Development · doi:10.1101/gad.12.2.149 · Cited by 2,476 · see citing works
A novel bHLH-PAS factor with close sequence similarity to hypoxia-inducible factor 1α regulates the VEGF expression and is potentially involved in lung and vascular development
Ema, M., Taya, S., Yokotani, N., Sogawa, K., Matsuda, Y., & Fujii-Kuriyama, Y. (1997) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.94.9.4273 · Cited by 1,016 · see citing works
Increased Vascularization in Mice Overexpressing Angiopoietin-1
Suri, C., McClain, J., Thurston, G., McDonald, D. M., Zhou, H., Oldmixon, E. H., Sato, T. N., & Yancopoulos, G. D. (1998) · Science · doi:10.1126/science.282.5388.468 · Cited by 818 · see citing works

Flagged first, then by citations

Research works printed but not linked: 8

[7]Quinn, T. P., Peters, K. G., De Vries, C., Ferrara, N. & Williams, L. T. (1993) Proc. Natl. Acad. Sci. USA 90, 7533-7537.
[10]Fong, G.-H., Zhang, L., Bryce, D.-M. & Peng, J. (1999) Development (Cambridge, U.K.) 126, 3015-3025.
[13]Kawasaki, T., Kitsukawa, T., Bekku, Y., Matsuda, Y., Sanbo, M., Yagi, T. & Fujisawa, H. (1999) Development (Cambridge, U.K.) 126, 4895-4902.
[22]Cao, Y., Linden, P., Farnebo, J., Cao, R., Eriksson, A., Kumar, V., Qi, J. H., Claesson-Welsh, L. & Alitalo, K. (1998) Proc. Natl. Acad. Sci. USA 95, 14389-14394.
[32]Ema, M., Taya, S., Yokotani, N., Sogawa, K., Matsuda, Y. & Fujii-Kuriyama, Y. (1997) Proc. Natl. Acad. Sci. USA 94, 4273-4278.
[37]Wurst, W. & Joyner, A. L. (1993) in Gene Targeting , ed. Joyner, A. L. (Oxford Univ. Press, New York), pp. 33-61.
[39]Nagy, A., Rossant, J., Nagy, R., Abramow-Newerly, W. & Roder, J. C. (1993) Proc. Natl. Acad. Sci. USA 90, 8424-8428.
[40]Baldwin, H. S., Shen, H. M., Yan, H. C., DeLisser, H. M., Chung, A., Mickanin, C., Trask, T., Kirschbaum, N. E., Newman, P. J., Albelda, S. M., et al . (1994) Development (Cambridge, U.K.) 120, 2539-2553.

Sorted by citations

Hypoxia — a key regulatory factor in tumour growth
Harris, A. L. (2002) · Nature Reviews Cancer · doi:10.1038/nrc704 · Cited by 5,177 · see citing works
Hypoxia-inducible factors in physiology and medicine
Semenza, G. L. (2012) · Cell · doi:10.1016/j.cell.2012.01.021 · Cited by 3,645 · see citing works
“5 with vascular defects (Peng et al., 2000) or bradycardia due to deficient catecholamine production (Tian et al.”
BackgroundInfluential
Regulation of angiogenesis by hypoxia: role of the HIF system
Pugh, C. W., & Ratcliffe, P. J. (2003) · Nature Medicine · doi:10.1038/nm0603-677 · Cited by 2,520 · see citing works
HIF1α and HIF2α: sibling rivalry in hypoxic tumour growth and progression
Keith, B., Johnson, R. S., & Simon, M. C. (2012) · Nature Reviews Cancer · doi:10.1038/nrc3183 · Cited by 1,693 · see citing works
Asparagine Hydroxylation of the HIF Transactivation Domain: A Hypoxic Switch
Lando, D., Peet, D. J., Whelan, D. A., Gorman, J. J., & Whitelaw, M. L. (2002) · Science · doi:10.1126/science.1068592 · Cited by 1,558 · see citing works
Differential Roles of Hypoxia-Inducible Factor 1α (HIF-1α) and HIF-2α in Hypoxic Gene Regulation
Hu, C.-J., Wang, L.-Y., Chodosh, L. A., Keith, B., & Simon, M. C. (2003) · Molecular and Cellular Biology · doi:10.1128/mcb.23.24.9361-9374.2003 · Cited by 1,386 · see citing works
“Besides the described similarities, HIF-2 gene targeting experiments also demonstrate that HIF-2 regulates the expression of several hypoxia-inducible genes, including those for tyrosine hydroxylase in the organ of Zuckerkandl (78, 100) and VEGF in type II pneumocytes in vivo (19).”
Hypoxia‐inducible factors in stem cells and cancer
Mazumdar, J., Dondeti, V. R., & Simon, M. C. (2009) · Journal of Cellular and Molecular Medicine · doi:10.1111/j.1582-4934.2009.00963.x · Cited by 127 · see citing works
Cellular adaptation to hypoxia: O 2 ‐sensing protein hydroxylases, hypoxia‐inducible transcription factors, and O 2 ‐regulated gene expression
Wenger, R. H. (2002) · The FASEB Journal · doi:10.1096/fj.01-0944rev · Cited by 1,135 · see citing works
Hypoxia-Induced Angiogenesis: Good and Evil
Krock, B. L., Skuli, N., & Simon, M. C. (2011) · Genes & Cancer · doi:10.1177/1947601911423654 · Cited by 1,179 · see citing works
Hypoxia-Inducible Factor-1 (HIF-1)
Ke, Q., & Costa, M. (2006) · Molecular Pharmacology · doi:10.1124/mol.106.027029 · Cited by 1,638 · see citing works
“Knockout of either HIF-1 (Iyer et al., 1998; Ryan et al., 1998; Kotch et al., 1999), HIF-2 (Tian et al., 1998; Peng et al., 2000), or HIF-1 (Maltepe et al., 1997) resulted in abnormal vascular development and lethality in mice.”
BackgroundInfluential
The role of oxygen availability in embryonic development and stem cell function
Simon, M. C., & Keith, B. (2008) · Nature Reviews Molecular Cell Biology · doi:10.1038/nrm2354 · Cited by 966 · see citing works
“Hif2α −/− embryos generated in another background (129Sv/Sv-CP) developed severe vascular defects in both the yolk sac and embryo itsel”
Background
Hydroxylation of HIF-1: Oxygen Sensing at the Molecular Level
Semenza, G. L. (2004) · Physiology · doi:10.1152/physiol.00001.2004 · Cited by 901 · see citing works
Hypoxia-inducible factor 1: oxygen homeostasis and disease pathophysiology
Semenza, G. L. (2001) · Trends in Molecular Medicine · doi:10.1016/s1471-4914(01)02090-1 · Cited by 930 · see citing works
The hypoxic tumour microenvironment
Petrova, V., Annicchiarico‐Petruzzelli, M., Melino, G., & Amelio, I. (2018) · Oncogenesis · doi:10.1038/s41389-017-0011-9 · Cited by 1,035 · see citing works
Heterozygous Deficiency of PHD2 Restores Tumor Oxygenation and Inhibits Metastasis via Endothelial Normalization
Mazzone, M., Dettori, D., de Oliveira, R. L., Loges, S., Schmidt, T., Jonckx, B., Tian, Y.-M., Lanahan, A. A., Pollard, P. J., de Almodóvar, C. R., et al. (2009) · Cell · doi:10.1016/j.cell.2009.01.020 · Cited by 803 · see citing works
“Consistent herewith, reduction of HIF-2a impairs vessel morphogenesis (Peng et al., 2000) and induces aberrant vascular networks (Yamashita et al.”
Regulation of erythropoiesis by hypoxia-inducible factors
Haase, V. H. (2013) · Blood Reviews · doi:10.1016/j.blre.2012.12.003 · Cited by 787 · see citing works
Hypoxia: A key regulator of angiogenesis in cancer
Liao, D., & Johnson, R. S. (2007) · Cancer and Metastasis Reviews · doi:10.1007/s10555-007-9066-y · Cited by 720 · see citing works
“HIF-2α is predominantly expressed in endothelial cells, although there its’ function is unclear [16, 17].”
Background
Recruitment of HIF-1α and HIF-2α to common target genes is differentially regulated in neuroblastoma: HIF-2α promotes an aggressive phenotype
Holmquist-Mengelbier, L., Fredlund, E., Löfstedt, T., Noguera, R., Navarro, S., Nilsson, H., Pietras, A., Vallon-Christersson, J., Borg, Å., Gradin, K., et al. (2006) · Cancer Cell · doi:10.1016/j.ccr.2006.08.026 · Cited by 735 · see citing works
Therapeutic targeting of hypoxia and hypoxia-inducible factors in cancer
Wigerup, C., Påhlman, S., & Bexell, D. (2016) · Pharmacology & Therapeutics · doi:10.1016/j.pharmthera.2016.04.009 · Cited by 687 · see citing works
“We recently showed that hypoxia-inducedHIF2A transcription in neuroblastoma cells is highly dependent on PI3K-mTORC2 but not PI3K-mTORC1, further supporting the hypothesis that targeting this pathway abrogates HIF activity (Mohlin et al., 2015).”
Influential
HIF-2α Promotes Hypoxic Cell Proliferation by Enhancing c-Myc Transcriptional Activity
Gordan, J. D., Bertout, J. A., Hu, C.-J., Diehl, J. A., & Simon, M. C. (2007) · Cancer Cell · doi:10.1016/j.ccr.2007.02.006 · Cited by 781 · see citing works
“…lethality due to bradycardia and vascular defects, perinatal lethality due to impaired lung maturation, and embryonic and postnatal lethality caused by multiorgan failure and mitochondrial dysfunction (Compernolle et al., 2002; Peng et al., 2000; Scortegagna et al., 2003; Tian et al., 1998).”
Background
The Role of Hypoxia in Development of the Mammalian Embryo
Dunwoodie, S. L. (2009) · Developmental Cell · doi:10.1016/j.devcel.2009.11.008 · Cited by 651 · see citing works
Angiogenesis in rheumatoid arthritis.
Paleolog, E. M. (2002) · Arthritis Research · doi:10.1186/ar575 · Cited by 354 · see citing works
Passing the baton: the HIF switch
Koh, M. Y., & Powis, G. (2012) · Trends in Biochemical Sciences · doi:10.1016/j.tibs.2012.06.004 · Cited by 589 · see citing works
The mammalian basic helix–loop–helix/PAS family of transcriptional regulators
Kewley, R. J., Whitelaw, M. L., & Chapman‐Smith, A. (2003) · The International Journal of Biochemistry & Cell Biology · doi:10.1016/s1357-2725(03)00211-5 · Cited by 590 · see citing works
Hypoxia-inducible factor-2 (HIF-2) regulates hepatic erythropoietin in vivo
Rankin, E. B., Biju, M. P., Liu, Q., Unger, T. L., Rha, J., Johnson, R. S., Simon, M. C., Keith, B., & Haase, V. H. (2007) · Journal of Clinical Investigation · doi:10.1172/jci30117 · Cited by 596 · see citing works
HIF1 and oxygen sensing in the brain
Sharp, F. R., & Bernaudin, M. (2004) · Nature reviews. Neuroscience · doi:10.1038/nrn1408 · Cited by 569 · see citing works
Genome-wide Association of Hypoxia-inducible Factor (HIF)-1α and HIF-2α DNA Binding with Expression Profiling of Hypoxia-inducible Transcripts
Mole, D. R., Blancher, C., Copley, R. R., Pollard, P. J., Gleadle, J. M., Ragoussis, J., & Ratcliffe, P. J. (2009) · Journal of Biological Chemistry · doi:10.1074/jbc.m901790200 · Cited by 552 · see citing works
Loss of HIF-2α and inhibition of VEGF impair fetal lung maturation, whereas treatment with VEGF prevents fatal respiratory distress in premature mice
Compernolle, V., Brusselmans, K., Acker, T., Hoet, P., Tjwa, M., Beck, H., Plaisance, S., Dor, Y., Keshet, E., Lupu, F., et al. (2002) · Nature Medicine · doi:10.1038/nm721 · Cited by 733 · see citing works
HIF-2α, but not HIF-1α, promotes iron absorption in mice
Mastrogiannaki, M., Matak, P., Keith, B., Simon, M. C., Vaulont, S., & Peyssonnaux, C. (2009) · Journal of Clinical Investigation · doi:10.1172/jci38499 · Cited by 502 · see citing works
Multiple organ pathology, metabolic abnormalities and impaired homeostasis of reactive oxygen species in Epas1−/− mice.
Scortegagna, M., Ding, K., Oktay, Y., Gaur, A., Thurmond, F., Yan, L.-J., Marck, B. T., Matsumoto, A. M., Shelton, J. M., Richardson, J. A., et al. (2003) · Nature Genetics · doi:10.1038/ng1266 · Cited by 496 · see citing works
Hypoxia-inducible factors: central regulators of the tumor phenotype
Gordan, J. D., & Simon, M. C. (2007) · Current Opinion in Genetics & Development · doi:10.1016/j.gde.2006.12.006 · Cited by 450 · see citing works
Regulation of angiogenesis by hypoxia-inducible factor 1
Hirota, K., & Semenza, G. L. (2006) · Critical Reviews in Oncology/Hematology · doi:10.1016/j.critrevonc.2005.12.003 · Cited by 466 · see citing works
Hypoxia-inducible factor 2α regulates macrophage function in mouse models of acute and tumor inflammation
Imtiyaz, H. Z., Williams, E. P., Hickey, M. M., Patel, S. A., Durham, A. C., Yuan, L.-J., Hammond, R., Gimotty, P. A., Keith, B., & Simon, M. C. (2010) · Journal of Clinical Investigation · doi:10.1172/jci39506 · Cited by 461 · see citing works
Acute postnatal ablation of Hif-2 α results in anemia
Gruber, M., Hu, C.-J., Johnson, R. S., Brown, E. J., Keith, B., & Simon, M. C. (2007) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0608382104 · Cited by 457 · see citing works
Direct protein–protein interaction between the intracellular domain of TRA-2 and the transcription factor TRA-1A modulates feminizing activity in C. elegansPreprint
Lum, D. H., Kuwabara, P. E., Zarkower, D. A., & Spence, A. M. (2000) · Genes & Development · doi:10.1101/gad.853700 · Cited by 392 · see citing works
“3200 GENES & DEVELOPMENT have been described in previous experiments (George et al. 1997; Peng et al. 2000).”
Method
Tie receptors: new modulators of angiogenic and lymphangiogenic responses
Jones, N., Iljin, K., Dumont, D., & Alitalo, K. K. (2001) · Nature Reviews Molecular Cell Biology · doi:10.1038/35067005 · Cited by 412 · see citing works
Regulation of Osteogenesis-Angiogenesis Coupling by HIFs and VEGF
Schipani, E., Maes, C., Carmeliet, G., & Semenza, G. L. (2009) · Journal of Bone and Mineral Research · doi:10.1359/jbmr.090602 · Cited by 407 · see citing works
Placental but Not Heart Defects Are Associated with Elevated Hypoxia-Inducible Factor α Levels in Mice Lacking Prolyl Hydroxylase Domain Protein 2
Takeda, K., Ho, V. C., Takeda, H., Duan, L.-J., Nagy, A., & Fong, G.-H. (2006) · Molecular and Cellular Biology · doi:10.1128/mcb.00425-06 · Cited by 401 · see citing works
“In mice, several gene targeting studies have shown the essential roles of both HIF-1 (12, 29) and HIF-2 (25, 33) during embryonic development, but the roles of PHDs are not yet known.”
BackgroundSelf-citation
Hypoxia alters gene expression in human neuroblastoma cells toward an immature and neural crest-like phenotype
Jögi, A., Øra, I., Nilsson, H., Lindeheim, Å., Makino, Y., Poellinger, L., Axelson, H., & Påhlman, S. (2002) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.102660199 · Cited by 399 · see citing works
Differentiating the functional role of hypoxia‐inducible factor (HIF)‐1α and HIF‐2α (EPAS‐1) by the use of RNA interference: erythropoietin is a HIF‐2α target gene in Hep3B and Kelly cells
Warnecke, C., Zaborowska, Z., Kurreck, J., Erdmann, V. A., Frei, U. A., Wiesener, M. S., & Eckardt, K. (2004) · The FASEB Journal · doi:10.1096/fj.04-1640fje · Cited by 395 · see citing works
“Inactivation of the HIF-2α gene was also lethal but attributed to bradycardia due to a defect in fetal catecholamine synthesis or improper remodeling of the primary vasculature during development (15, 16).”
Background
Prolonged Hypoxia Differentially Regulates Hypoxia-inducible Factor (HIF)-1α and HIF-2α Expression in Lung Epithelial Cells
Uchida, T., Rossignol, F., Matthay, M. A., Mounier, R., Couette, S., Clottes, E., & Clérici, C. (2004) · Journal of Biological Chemistry · doi:10.1074/jbc.m400461200 · Cited by 429 · see citing works
The biology of hypoxia: the role of oxygen sensing in development, normal function, and disease
Giaccia, A. J., Simon, M. C., & Johnson, R. (2004) · Genes & Development · doi:10.1101/gad.1243304 · Cited by 380 · see citing works
“…die at day 12.5 of gestation due to pronounced bradycardia related to substantially decreased catecholamine levels; although at least one other group found that the loss of viability was instead related to defective vascularization (Tian et al. 1998; Peng et al. 2000; Compernolle et al. 2002).”
Influential
Structural integration in hypoxia-inducible factors
Wu, D., Potluri, N., Lu, J., Kim, Y., & Rastinejad, F. (2015) · Nature · doi:10.1038/nature14883 · Cited by 346 · see citing works
Mammalian Per-Arnt-Sim Proteins in Environmental Adaptation
McIntosh, B. E., Hogenesch, J. B., & Bradfield, C. A. (2010) · Annual Review of Physiology · doi:10.1146/annurev-physiol-021909-135922 · Cited by 352 · see citing works
Biology of hypoxia-inducible factor-2α in development and disease
Patel, S. A., & Simon, M. C. (2008) · Cell Death and Differentiation · doi:10.1038/cdd.2008.17 · Cited by 325 · see citing works
Generating specificity and diversity in the transcriptional response to hypoxia
Lendahl, U., Lee, K. L., Yang, H. H., & Poellinger, L. (2009) · Nature Reviews Genetics · doi:10.1038/nrg2665 · Cited by 330 · see citing works
Hypoxic regulation of erythropoiesis and iron metabolism
Haase, V. H. (2010) · American Journal of Physiology-Renal Physiology · doi:10.1152/ajprenal.00174.2010 · Cited by 347 · see citing works
HMG-CoA Reductase Inhibitors Regulate Inflammatory Transcription Factors in Human Endothelial and Vascular Smooth Muscle Cells
Dichtl, W., Dulak, J., Frick, M., Alber, H., Schwarzacher, S., Ares, M., Nilsson, J., Pachinger, O., & Weidinger, F. (2003) · Arteriosclerosis, Thrombosis and Vascular Biology · doi:10.1161/01.atv.0000043456.48735.20 · Cited by 345 · see citing works
Oxygen sensors and angiogenesis
Maxwell, P. H., & Ratcliffe, P. J. (2002) · Seminars in Cell and Developmental Biology · doi:10.1006/scdb.2001.0287 · Cited by 328 · see citing works
Hypoxia-inducible factors in the kidney
Haase, V. H. (2006) · American Journal of Physiology-Renal Physiology · doi:10.1152/ajprenal.00071.2006 · Cited by 329 · see citing works
“5 (86); and d) exhibited defective ROS scavenging, resulting in hepatic steatosis, cardiac hypertrophy, skeletal myopathy, hypocellular bone marrow and mitochondrial abnormalities (106).”
Background
The N-Terminal Transactivation Domain Confers Target Gene Specificity of Hypoxia-inducible Factors HIF-1α and HIF-2α
Hu, C.-J., Sataur, A., Wang, L., Chen, H., & Simon, M. C. (2007) · Molecular Biology of the Cell · doi:10.1091/mbc.e06-05-0419 · Cited by 355 · see citing works
“Based on these properties, it has been suggested that HIF-1 and HIF-2 play related roles in hypoxic responses, and the unique phenotypes observed in Hif- mutant mice are due to their distinct expression patterns during development (Tian et al., 1998; Peng et al., 2000; Compernolle et al., 2002).”
Background
Heterozygous deficiency of hypoxia-inducible factor–2α protects mice against pulmonary hypertension and right ventricular dysfunction during prolonged hypoxia
Brusselmans, K., Compernolle, V., Tjwa, M., Wiesener, M. S., Maxwell, P. H., Collen, D., & Carmeliet, P. (2003) · Journal of Clinical Investigation · doi:10.1172/jci15496 · Cited by 316 · see citing works
“Since homozygous deficient Hif2α–/– mice died during gestation or immediately after birth (21, 22, 25), viable heterozygous Hif2α+/– mice were used in the present study to analyze the role of HIF-2α during pulmonary hypertension and vascular remodeling.”
BackgroundMethodResult
Regulation of the Pulmonary Circulation in the Fetus and Newborn
Gao, Y., & Raj, J. U. (2010) · Physiological Reviews · doi:10.1152/physrev.00032.2009 · Cited by 349 · see citing works
“HIF-2 / mouse embryos die as a consequence of inadequate blood vessel fusion and remodeling, impaired fetal lung maturation, and a very slow heart rate because of insufficient catecholamine production (452, 569).”
Background
Ischemia and Reperfusion Injury in Kidney Transplantation: Relevant Mechanisms in Injury and Repair
Nieuwenhuijs‐Moeke, G. J., Pischke, S. E., Berger, S. P., Sanders, J., Pol, R. A., Struys, M. M. R. F., Ploeg, R. J., & Leuvenink, H. G. D. (2020) · Journal of Clinical Medicine · doi:10.3390/jcm9010253 · Cited by 332 · see citing works
Regulation of Angiogenesis by Hypoxia and Hypoxia‐Inducible Factors
Hickey, M. M., & Simon, M. C. (2006) · Current topics in developmental biology/Current Topics in Developmental Biology · doi:10.1016/s0070-2153(06)76007-0 · Cited by 268 · see citing works
Cooperative Interaction of Hypoxia-inducible Factor-2α (HIF-2α) and Ets-1 in the Transcriptional Activation of Vascular Endothelial Growth Factor Receptor-2 (Flk-1)
Elvert, G., Kappel, A., Heidenreich, R., Englmeier, U., Lanz, S., Acker, T., Rauter, M., Plate, K. H., Sieweke, M. H., Breier, G., et al. (2003) · Journal of Biological Chemistry · doi:10.1074/jbc.m211298200 · Cited by 272 · see citing works
miRNAs regulate the HIF switch during hypoxia: a novel therapeutic target
Serocki, M., Bartoszewska, S., Janaszak-Jasiecka, A., Ochocka, R. J., Collawn, J. F., & Bartoszewski, R. (2018) · Angiogenesis · doi:10.1007/s10456-018-9600-2 · Cited by 288 · see citing works
“Importantly, HIF-2α knockout mice did not show impaired blood vessels formation by vasculogenesis, but later fusion and assembly, suggesting that HIF-2α activity is critical for the remodeling of the primary vascular network into a mature hierarchy pattern [52].”
Background
O2-regulated gene expression: transcriptional control of cardiorespiratory physiology by HIF-1
Semenza, G. L. (2004) · Journal of Applied Physiology · doi:10.1152/japplphysiol.00770.2003 · Cited by 268 · see citing works
Iron-regulatory proteins limit hypoxia-inducible factor-2α expression in iron deficiency
Sanchez, M., Galy, B., Muckenthaler, M. U., & Hentze, M. W. (2007) · Nature Structural & Molecular Biology · doi:10.1038/nsmb1222 · Cited by 294 · see citing works
Inhibition of Hypoxia Inducible Factor Hydroxylases Protects Against Renal Ischemia-Reperfusion Injury
Hill, P., Shukla, D., Tran, M. G. B., Aragonés, J., Cook, H. T., Carmeliet, P., & Maxwell, P. H. (2008) · Journal of the American Society of Nephrology · doi:10.1681/asn.2006090998 · Cited by 280 · see citing works
The hypoxia-inducible factors: key transcriptional regulators of hypoxic responses
Bracken, C. P., Whitelaw, M. L., & Peet, D. J. (2003) · Cellular and Molecular Life Sciences · doi:10.1007/s00018-003-2370-y · Cited by 255 · see citing works
Vascular Abnormalities and Elevated Blood Pressure in Mice Lacking Adrenomedullin Gene
Shindo, T., Kurihara, Y., Nishimatsu, H., Moriyama, N., Kakoki, M., Wang, Y.-H., Imai, Y., Ebihara, A., Kuwaki, T., Ju, K., et al. (2001) · Circulation · doi:10.1161/hc4101.097111 · Cited by 273 · see citing works
Cloning, expression analysis, and chromosomal localization of murine and human homologues of aXenopus Mix gene
Robb, L. G., Hartley, L., Begley, C. G., Brodnicki, T. C., Copeland, N. G., Gilbert, D. J., Jenkins, N. A., & Elefanty, A. G. (2000) · Developmental Dynamics · doi:10.1002/1097-0177(2000)9999:9999 · Cited by 78 · see citing works
Hypoxia, hypoxia-inducible factors (HIF), HIF hydroxylases and oxygen sensing
Webb, J. D., Coleman, M. L., & Pugh, C. W. (2009) · Cellular and Molecular Life Sciences · doi:10.1007/s00018-009-0147-7 · Cited by 255 · see citing works
“HIF-2 alpha inactivation has been reported to cause diverse phenotypes in the context of different genetic backgrounds, with death occurring in utero with defective catecholamine production [71] or vascularisation [72] or a few days or weeks after birth due to respiratory distress [73] or mitochondrial dysfunction [74…”
Background
Differential Regulation of the Transcriptional Activities of Hypoxia-Inducible Factor 1 Alpha (HIF-1α) and HIF-2α in Stem Cells
Hu, C., Iyer, S. R., Sataur, A., Covello, K. L., Chodosh, L. A., & Simon, M. C. (2006) · Molecular and Cellular Biology · doi:10.1128/mcb.26.9.3514-3526.2006 · Cited by 267 · see citing works
“HIF is required for normal embryonic development; ablation of hypoxic responses via targeted deletion of the Hif- and Arnt genes leads to embryonic lethality (1, 7, 18, 30, 36, 39, 46).”
Background
Hypoxia as a key player in the AKI-to-CKD transition
Tanaka, S., Tanaka, T., & Nangaku, M. (2014) · American Journal of Physiology-Renal Physiology · doi:10.1152/ajprenal.00425.2014 · Cited by 280 · see citing works
Hypoxia and Fetal Heart Development
Patterson, A. J., & Zhang, L. (2010) · Current Molecular Medicine · doi:10.2174/156652410792630643 · Cited by 240 · see citing works
“Little is known about the role of HIF-2 in heart formation and development, although HIF-2α knockout impairs vascular development as well as altered cardiac rhythm due to the deregulation of catecholamine release [79].”
BackgroundSelf-citation
Hypoxia-Driven Immune Escape in the Tumor Microenvironment
Vito, A., El-Sayes, N., & Mossman, K. L. (2020) · Cells · doi:10.3390/cells9040992 · Cited by 274 · see citing works
“Peng and colleagues have shown that EPAS1 plays an important role in controlling vascular remodeling and that the protein level of EPAS1 is regulated by oxygen tension, where hypoxia induces stabilization of the protein [12].”
Background
HLF/HIF‐2α is a key factor in retinopathy of prematurity in association with erythropoietin
Morita, M., Ohneda, O., Yamashita, T., Takahashi, S., Suzuki, N., Nakajima, O., Kawauchi, S., Ema, M., Shibahara, S., Udono, T., et al. (2003) · The EMBO Journal · doi:10.1093/emboj/cdg117 · Cited by 230 · see citing works
Essential role for prolyl hydroxylase domain protein 2 in oxygen homeostasis of the adult vascular system
Takeda, K., Cowan, A., & Fong, G.-H. (2007) · Circulation · doi:10.1161/circulationaha.107.701516 · Cited by 236 · see citing works
Self-citation
Failure to prolyl hydroxylate hypoxia‐inducible factor α phenocopies VHL inactivation in vivo
Kim, W. Y., Safran, M., Buckley, M. R., Ebert, B. L., Glickman, J., Bosenberg, M., Regan, M., & Kaelin, W. G. (2006) · The EMBO Journal · doi:10.1038/sj.emboj.7601300 · Cited by 235 · see citing works
“HIF2a / mice also exhibit embryonic or early postnatal lethality but as a consequence of catechola- mine deficiency or lung maturation defects (Tian et al, 1998; Peng et al, 2000; Compernolle et al, 2002).”
Background
Endothelial deletion of hypoxia-inducible factor–2α (HIF-2α) alters vascular function and tumor angiogenesis
Skuli, N., Liu, L., Runge, A., Wang, T., Yuan, L., Patel, S., Iruela‐Arispe, M. L., Simon, M. C., & Keith, B. (2009) · Blood · doi:10.1182/blood-2008-12-193581 · Cited by 256 · see citing works
Curcumin Inhibits Hypoxia-Inducible Factor-1 by Degrading Aryl Hydrocarbon Receptor Nuclear Translocator: A Mechanism of Tumor Growth Inhibition
Choi, H., Chun, Y., Kim, S.-W., Kim, M.-S., & Park, J. (2006) · Molecular Pharmacology · doi:10.1124/mol.106.025817 · Cited by 219 · see citing works
“However, in addition to HIF-1 , many cancer cells have also HIF-2 (alternatively named EPAS-1 or MOP2) (Peng et al., 2000).”
Background
Cobalt promotes angiogenesis via hypoxia-inducible factor and protects tubulointerstitium in the remnant kidney model
Tanaka, T., Kojima, I., Ohse, T., Ingelfinger, J. R., Adler, S., Fujita, T., & Nangaku, M. (2005) · Laboratory Investigation · doi:10.1038/labinvest.3700328 · Cited by 238 · see citing works
“To date, several studies using HIF-2 α knockout mice revealed divergent properties, including impairment in remodeling of the primary vascular networks at postvasculogenesis stages”
Background
Vasculogenesis and Angiogenesis
Patan, S. (2004) · Cancer treatment and research · doi:10.1007/978-1-4419-8871-3_1 · Cited by 430 · see citing works
Interferons and progesterone for establishment and maintenance of pregnancy: interactions among novel cell signaling pathways
Bazer, F. W., Burghardt, R. C., Johnson, G. A., Spencer, T. E., & Wu, G. (2008) · Reproductive Biology · doi:10.1016/s1642-431x(12)60012-6 · Cited by 231 · see citing works
“Mice with lacking Hif1a, Hif2a or Hif1b (Arnt) die at mid-gestation due to vascular defects in the embryo and placenta [5, 31, 74, 89, 101, 117, 140].”
Background
Abnormal Sympathoadrenal Development and Systemic Hypotension in PHD3−/− Mice
Bishop, T., Gallagher, D., Pascual, A., Lygate, C. A., de Bono, J. P., Nicholls, L. G., Ortega‐Sáenz, P., Oster, H., Wijeyekoon, B., Sutherland, A., et al. (2008) · Molecular and Cellular Biology · doi:10.1128/mcb.02041-07 · Cited by 181 · see citing works
“Since homozygous inactivation of HIF-1 or HIF-2 results in embryonic lethality (20, 33 , 34, 42), we analyzed the effects of heterozygous inactivation by generating appropriate crosses with PHD3/ animals to allow for littermate comparisons.”
Background
Hypoxia-Inducible Factor as an Angiogenic Master Switch
Hashimoto, T., & Shibasaki, F. (2015) · Frontiers in Pediatrics · doi:10.3389/fped.2015.00033 · Cited by 231 · see citing works
“On the other hand, Hif-2α−/− mice manifest defective vascular remodeling during embryonic development (63), as well as defective catecholamine homeostasis (64), fetal lung maturation, and hematopoietic cell production (65).”
Background
Genetic evidence for a tumor suppressor role of HIF-2α
Acker, T., Díez‐Juan, A., Aragonés, J., Tjwa, M., Brusselmans, K., Moons, L., Fukumura, D., Moreno-Murciano, P., Herbert, J., Burger, A. M., et al. (2005) · Cancer Cell · doi:10.1016/j.ccr.2005.07.003 · Cited by 184 · see citing works
Mechanisms of adaptive angiogenesis to tissue hypoxia
Fong, G. (2008) · Angiogenesis · doi:10.1007/s10456-008-9107-3 · Cited by 201 · see citing works
Self-citation
Hypoxia-Inducible Factors 1α and 2α Regulate Trophoblast Differentiation
Dahl, K. D. C., Fryer, B. H., Mack, F. A., Compernolle, V., Maltepe, E., Adelman, D. M., Carmeliet, P., & Simon, M. C. (2005) · Molecular and Cellular Biology · doi:10.1128/mcb.25.23.10479-10491.2005 · Cited by 228 · see citing works
“However, three independent lines of HIF2 -deficient mice display a wide array of phenotypes, most notably reduced circulating catecholamine levels, lung remodeling defects, and heart failure (9, 35, 47).”
Background
Defects in pulmonary vasculature and perinatal lung hemorrhage in mice heterozygous null for the Forkhead Box f1 transcription factor.
Kalinichenko, V., Lim, L., Stolz, D., Shin, B., Rausa, F., Clark, J., Whitsett, J., Watkins, S. C., & Costa, R. (2001) · Developmental Biology · doi:10.1006/dbio.2001.0322 · Cited by 196 · see citing works
Signalling pathways in vasculogenic mimicry.
Paulis, Y. W. J., Soetekouw, P., Verheul, H. M. W., Tjan-Heijnen, V., & Griffioen, A. (2010) · Biochimica et Biophysica Acta · doi:10.1016/j.bbcan.2010.01.001 · Cited by 194 · see citing works
“As HIF-2α expression is associated with developing endothelium [42], proper vascular development [43] and increased tumour malignancy [44,45], it may be an important protein for inducing tumour cell plasticity.”
HIF hydroxylation and cellular oxygen sensing
Metzen, E., & Ratcliffe, P. J. (2004) · Biological Chemistry · doi:10.1515/bc.2004.016 · Cited by 171 · see citing works
“Genetic inactivation of both HIF-1a and HIF-2a are both lethal but result in different phenotypes (Iyer et al., 1998; Ryan et al., 1998; Tian et al., 1998; Peng et al., 2000; Compernolle et al., 2002), indicating critical functions which are distinct and non-redundant.”
Background
Oxygen-Regulated Gene Expression in Bovine Blastocysts1
Harvey, A. J., Kind, K. L., Pantaleon, M., Armstrong, D. T., & Thompson, J. G. (2004) · Biology of Reproduction · doi:10.1095/biolreprod.104.028639 · Cited by 189 · see citing works
“5, developing severe vascular defects in both the yolk sac and embryo proper [32], suggesting that HIFs are regulators of critical developmental processes associated with normal postimplantation embryo development.”
Background
Oxygen-dependent and tissue-specific regulation of erythropoietin gene expression
Fandrey, J. (2004) · American Journal of Physiology-Regulatory, Integrative and Comparative Physiology · doi:10.1152/ajpregu.00577.2003 · Cited by 243 · see citing works
“Whereas HIF-1 / mice die around midgestation due to severe cardiovascular and central nervous system (CNS) malformations (64, 125), three different phenotypes for HIF-2 / mice (perhaps depending on the genetic background) were observed (18, 117, 148).”
Background
From oxygen to erythropoietin: Relevance of hypoxia for retinal development, health and disease
Caprara, C., & Grimm, C. (2012) · Progress in Retinal and Eye Research · doi:10.1016/j.preteyeres.2011.11.003 · Cited by 176 · see citing works
Potential Role of Natural Compounds as Anti-Angiogenic Agents in Cancer
Shanmugam, M. K., Warrier, S. R., Kumar, A. P., Sethi, G., & Arfuso, F. (2017) · Current Vascular Pharmacology · doi:10.2174/1570161115666170713094319 · Cited by 213 · see citing works
Endothelial HIF-2 mediates protection and recovery from ischemic kidney injury
Kapitsinou, P. P., Sano, H., Michael, M., Kobayashi, H., Davidoff, O., Bian, A., Yao, B., Zhang, M.-Z., Harris, R. C., Duffy, K. J., et al. (2014) · Journal of Clinical Investigation · doi:10.1172/jci69073 · Cited by 187 · see citing works
Hypoxia‐inducible factor as a physiological regulator
Maxwell, P. H. (2005) · Experimental Physiology · doi:10.1113/expphysiol.2005.030924 · Cited by 164 · see citing works
“Second, HIF-2α has a more specialized role, being important in yolk sac vascularization, development and function of the autonomic nervous system, and surfactant formation in the lung at birth (Tian et al. 1998; Peng et al. 2000; Compernolle et al. 2002).”
Background
HYPOXIA‐INDUCED ERYTHROPOIETIN PRODUCTION: A PARADIGM FOR OXYGEN‐REGULATED GENE EXPRESSION
Stockmann, C., & Fandrey, J. (2006) · Clinical and Experimental Pharmacology and Physiology · doi:10.1111/j.1440-1681.2006.04474.x · Cited by 154 · see citing works
Role of ETS Transcription Factors in the Hypoxia-Inducible Factor-2 Target Gene Selection
Aprelikova, O. N., Wood, M. J. A., Tackett, S. A., Chandramouli, G. V. R., & Barrett, J. C. (2006) · Cancer Research · doi:10.1158/0008-5472.can-05-3345 · Cited by 156 · see citing works
Hypoxia Inducible Factor Pathway and Physiological Adaptation: A Cell Survival Pathway?
Kumar, H., & Choi, D. (2015) · Mediators of Inflammation · doi:10.1155/2015/584758 · Cited by 183 · see citing works
“More research is needed to clarify the paradoxical ROS formation in the response of tissues to hypoxia.”
Background
Hypoxia-Induced Gene Expression Occurs Solely through the Action of Hypoxia-Inducible Factor 1α (HIF-1α): Role of Cytoplasmic Trapping of HIF-2α
Park, S.-K., Dadak, A. M., Haase, V. H., Fontana, L., Giaccia, A. J., & Johnson, R. S. (2003) · Molecular and Cellular Biology · doi:10.1128/mcb.23.14.4959-4971.2003 · Cited by 170 · see citing works
“... expression of HIF-2 mRNA is observed in alveolar epithelial cells in lung, but the mRNA is also seen in endothelial cells of various tissues, such as brain, heart, kidney, and liver (5, 7). HIF-1/ embryos die before embryonic day 11.5 (E11.5) and display defects in neural fold formation, cephalic vascularization,…”
BackgroundInfluential
Endothelial PAS Domain Protein 1 Gene Promotes Angiogenesis Through the Transactivation of Both Vascular Endothelial Growth Factor and Its Receptor, Flt-1
Takeda, N., Maemura, K., Imai, Y., Harada, T., Kawanami, D., Nojiri, T., Manabe, I., & Nagai, R. (2004) · Circulation Research · doi:10.1161/01.res.0000134920.10128.b4 · Cited by 172 · see citing works
“EPAS1-(1-870) promotes capillary formation.”
BackgroundMethodInfluential
The Distinct Role of HIF-1α and HIF-2α in Hypoxia and Angiogenesis
Bakleh, M. Z., & Zen, A. A. H. (2025) · Cells · doi:10.3390/cells14090673 · Cited by 171 · see citing works
“HIF-2 α loss results in abnormal vessel remodeling in the embryo and yolk sac, which causes swelling and hemorrhage in the vessels [146].”
HIF in Kidney Disease and Development
Gunaratnam, L., & Bonventre, J. V. (2008) · Journal of the American Society of Nephrology · doi:10.1681/asn.2008070804 · Cited by 171 · see citing works
HIF-1 and hypoxic response: the plot thickens
Poellinger, L., & Johnson, R. S. (2003) · Current Opinion in Genetics & Development · doi:10.1016/j.gde.2003.12.006 · Cited by 149 · see citing works
Hypoxia increases sirtuin 1 expression in a hypoxia-inducible factor-dependent manner
Chen, R., Dioum, E. M., Hogg, R. T., Gerard, R. D., & Garcia, J. A. (2011) · Journal of Biological Chemistry · doi:10.1074/jbc.m110.175414 · Cited by 155 · see citing works
The role of hypoxia-inducible factors in cancer
Maynard, M. A., & Ohh, M. (2007) · Cellular and Molecular Life Sciences · doi:10.1007/s00018-007-7082-2 · Cited by 138 · see citing works

Authors: Peng, J., Zhang, L., Drysdale, L., & Fong, G.-H.
Affiliations: Western University (CA)
ORCID: Peng, Jun
Zhang, Liyong
Fong, Guo-Hua
Venue: Proceedings of the National Academy of Sciences
Publisher: National Academy of Sciences
Published: 2000-07-04
Volume: 97
Issue: 15
Pages: 8386-8391
ISSN: 0027-8424 (ISSN-L)
1091-6490
DOI: 10.1073/pnas.140087397
PMC: PMC26957
OpenAlex: W2124053736
Cited by: 460
References: 0
Citations by year: 2026: 4 · 2025: 8 · 2024: 9 · 2023: 13 · 2022: 8 · 2021: 11 · 2020: 10 · 2019: 14 · 2018: 7 · 2017: 9 · 2016: 9 · 2015: 22 · 2014: 19 · 2013: 19 · 2012: 19
FWCI: 7.00
Type: journal article
Language: en
Open access: green
europepmc.org
Locations: Proceedings of the National Academy of Sciences (publishedVersion)
Europe PMC (PubMed Central) (publishedVersion)
PubMed Central (publishedVersion)
PubMed (publishedVersion)
Topics: Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Angiogenesis and VEGF in Cancer
Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Developmental Biology and Gene Regulation
Life Sciences › Neuroscience › Neurology › Barrier Structure and Function Studies
Keywords: HIF-2α, vascular remodeling, vascular development, vasculogenesis, yolk sac vasculature, embryonic lethality, gene targeting, transcription factors
MeSH terms: Endothelial PAS Domain-Containing Protein 1, Animals, Cell Line, Female, Hemorrhage, Male, Mice, Inbred ICR, Trans-Activators, Helix-Loop-Helix Motifs, Mice, Knockout, Neovascularization, Physiologic, Mice, Basic Helix-Loop-Helix Transcription Factors, Basic Helix-Loop-Helix Proteins

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

What counts as a claim ›How we measure confidence ›How we check this ›

Are you an author, or do you see a problem with this page? Request a review

The transcription factor EPAS-1/hypoxia-inducible factor 2α plays an important role in vascular remodeling

Abstract

Integrity signals

Claims the paper makes

Claims other papers make about this one

Self-check

Cites

Cited by

Record

About these checks