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

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

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

DOI 10.1073/pnas.140087397PMC PMC26957

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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.

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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 270
“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 275
Hypoxia and Fetal Heart Development
Patterson, A. J., & Zhang, L. (2010) · Current Molecular Medicine · doi:10.2174/156652410792630643 · Cited by 244
“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 287
“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 232
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
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
“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 261
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
“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
“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 447
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 233
“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 186
“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 242
“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 187
Mechanisms of adaptive angiogenesis to tissue hypoxia
Fong, G. (2008) · Angiogenesis · doi:10.1007/s10456-008-9107-3 · Cited by 212
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 229
“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. V., Lim, L., Stolz, D. B., Shin, B., Rausa, F. M., Clark, J. C., Whitsett, J. A., Watkins, S. C., & Costa, R. H. (2001) · Developmental Biology · doi:10.1006/dbio.2001.0322 · Cited by 214
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
“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 175
“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
“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
“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
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 214
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 192
Hypoxia‐inducible factor as a physiological regulator
Maxwell, P. H. (2005) · Experimental Physiology · doi:10.1113/expphysiol.2005.030924 · Cited by 170
“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 159
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
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 192
“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
“... 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 174
“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 190
“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 178
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
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
The role of hypoxia-inducible factors in cancer
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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

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

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