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The transcription factor EPAS-1/hypoxia-inducible factor 2α plays an important role in vascular remodeling
Open accessAbstract
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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“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
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“Similar to MYC, HIF1 is also a driver for metabolic switch from oxidative to glycolysis by upregulating glucose transporters and most glycolytic enzymes such as HK II, phosphofructokinase 1 (PFK1), fructose-bisphosphate aldolase A (ALDOA), ENO1, PKM2, and LDHA, as well as pentose phosphate pathway (PPP) enzymes (Iyer…”
BackgroundInfluentialAttenuation of HIF-1 DNA-binding activity limits hypoxia-inducible endothelin-1 expression
Camenisch, G., Stroka, D., Gassmann, M., & Wenger, R. H. (2001) · Pflügers Archiv - European Journal of Physiology · doi:10.1007/s004240100679 · Cited by 73
Hodson, E. J., Nicholls, L. G., Turner, P. J., Llyr, R., Fielding, J. W., Douglas, G., Ratnayaka, I., Robbins, P. A., Pugh, C. W., Buckler, K. J., et al. (2015) · The Journal of Physiology · doi:10.1113/jp271050 · Cited by 84
“…Mazzone et al. 2009) – unlike their homozygous counterparts which are embryonic lethal (Carmeliet et al. 1998; Iyer et al. 1998; Kotch et al. 1999; Peng et al. 2000; Compernolle et al. 2002, 2003; Takeda et al. 2006) or, in the case of Hif-2α−/− mice, develop gross abnormalities even if they…”
BackgroundDaikoku, T., Matsumoto, H., Gupta, R. A., Das, S. K., Gassmann, M., DuBois, R. N., & Dey, S. K. (2003) · Journal of Biological Chemistry · doi:10.1074/jbc.m211390200 · Cited by 124
Role of Intestinal HIF-2α in Health and Disease
Ramakrishnan, S. K., & Shah, Y. M. (2015) · Annual Review of Physiology · doi:10.1146/annurev-physiol-021115-105202 · Cited by 100
“5 due to defects in vascular development and remodeling (55, 56).”
Hypoxia-inducible factors, hypoxia, and tumor angiogenesis
Gruber, M., & Simon, M. C. (2006) · Current Opinion in Hematology · doi:10.1097/01.moh.0000219663.88409.35 · Cited by 82
Podocyte Expression of Hypoxia-Inducible Factor (HIF)–1 and HIF–2 during Glomerular Development
Freeburg, P. B., Robert, B., John, P. L. S., & Abrahamson, D. R. (2003) · Journal of the American Society of Nephrology · doi:10.1097/01.asn.0000059308.82322.4f · Cited by 82
“Primers for HIF-2 RT-PCR were as described previously (12): HIF-2 forward primer 5'-AATGACAGCTGACAAGGAGAAAAA-3' and reverse primer 5'-GAGTGAAGTCAAAGATGCTGTGTC–3'.”
Tanaka, T., & Nangaku, M. (2009) · Current Opinion in Nephrology & Hypertension · doi:10.1097/mnh.0b013e3283328eed · Cited by 81
Morphological and molecular aspects of physiological vascular morphogenesis
Ribatti, D., Nico, B., & Crivellato, E. (2009) · Angiogenesis · doi:10.1007/s10456-008-9125-1 · Cited by 88
“The complete absence of HIF-2a leads to severe vascular defects in the yolk sac and embryo proper, and mutant embryos die by day 12.5, suggesting that HIF- 2a plays a critical role in controlling vascular remodeling during early embryonic development [ 90 ].”
BackgroundInfluentialUpdate on mutations in the HIF: EPO pathway and their role in erythrocytosis
Lappin, T. R. J., & Lee, F. S. (2019) · Blood Reviews · doi:10.1016/j.blre.2019.100590 · Cited by 86
Brandley, M. C., Young, R. L., Warren, D. L., Thompson, M. B., & Wagner, G. P. (2012) · Genome Biology and Evolution · doi:10.1093/gbe/evs013 · Cited by 76
“…1 (EPAS1) and hypoxia-inducible factor 1a (HIF1A) genes that activate VEGF expression in response to hypoxic conditions (Forsythe et al. 1996; Peng et al. 2000; Takeda et al. 2004); interleukin 20 receptor b (IL20RB), an inducer of endothelial cell proliferation (Gaspar et al. 2002; Hsieh et…”
BackgroundCellular reaction to hypoxia: sensing and responding to an adverse environment
Papandreou, I., Powell, A. A., Lim, A. L., & Denko, N. C. (2004) · Mutation research. Fundamental and molecular mechanisms of mutagenesis · doi:10.1016/j.mrfmmm.2004.06.054 · Cited by 77
Augstein, A., Poitz, D. M., Braun-Dullaeus, R. C., Strasser, R. H., & Schmeißer, A. (2010) · Cellular and Molecular Life Sciences · doi:10.1007/s00018-010-0575-4 · Cited by 69
“Beside the established function of HIF-1a in endothelial proliferation, migration and sprouting [9, 10], HIF-2a seems to participate more in remodeling and maturation of the microvasculature and maintaining the vessel integrity [11, 12].”
BackgroundYamamura, K., Uruno, T., Shiraishi, A., Tanaka, Y., Ushijima, M., Nakahara, T., Watanabe, M., Kido‐Nakahara, M., Tsuge, I., Furue, M., et al. (2017) · Nature Communications · doi:10.1038/ncomms13946 · Cited by 82
Partch, C. L., & Gardner, K. H. (2011) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1101357108 · Cited by 65
Chen, L., Uchida, K., Endler, A., & Shibasaki, F. (2007) · Journal of Biological Chemistry · doi:10.1074/jbc.m700423200 · Cited by 66
Cellular and molecular mechanisms of hypoxia-inducible factor driven vascular remodeling
Hänze, J., Weissmann, N., Grimminger, F., Seeger, W., & Rose, F. (2007) · Thrombosis and Haemostasis · doi:10.1160/th06-12-0744 · Cited by 73
The Role of Hypoxia in Stem Cell Potency and Differentiation
Hawkins, K. E., Sharp, T. V., & McKay, T. R. (2013) · Regenerative Medicine · doi:10.2217/rme.13.71 · Cited by 87
In vitro study of enhanced osteogenesis induced by HIF-1α-transduced bone marrow stem cells
Zou, D., Han, W., You, S., Ye, D., Wang, L., Wang, S., Zhao, J., Zhang, W., Jiang, X., Zhang, X., et al. (2011) · Cell Proliferation · doi:10.1111/j.1365-2184.2011.00747.x · Cited by 75
Cellular oxygen sensing in health and disease
Mole, D. R., & Ratcliffe, P. J. (2007) · Pediatric Nephrology · doi:10.1007/s00467-007-0632-x · Cited by 67
Bracken, C. P., Whitelaw, M. L., & Peet, D. J. (2005) · Journal of Biological Chemistry · doi:10.1074/jbc.m409987200 · Cited by 73
Hypoxic regulation of mRNA expression
Gardner, L. B., & Corn, P. (2008) · Cell Cycle · doi:10.4161/cc.7.13.6203 · Cited by 69
Nilsson, H., Jögi, A., Beckman, S., Harris, A. L., Poellinger, L., & Påhlman, S. (2005) · Experimental Cell Research · doi:10.1016/j.yexcr.2004.10.003 · Cited by 75
Bishop, T., Talbot, N. P., Turner, P. J., Nicholls, L. G., Pascual, A., Hodson, E. J., Douglas, G., Fielding, J. W., Smith, T. G., Demetriades, M., et al. (2013) · The Journal of Physiology · doi:10.1113/jphysiol.2012.247254 · Cited by 64
“Physiological analyses of mice with homozygous inactivation of HIF-1 α or HIF-2 α are confounded by embryonic lethal or severe neonatal/developmental phenotypes (Iyer et al. 1998; Tian et al. 1998; Kotch et al. 1999; Peng et al. 2000; Scortegagna et al. 2003).”
From stem cells to cancer stem cells: HIF takes the stage
Lee, K. E., & Simon, M. C. (2012) · Current Opinion in Cell Biology · doi:10.1016/j.ceb.2012.01.005 · Cited by 57
Life is a pattern: vascular assembly within the embryo
Heinke, J. (2011) · Frontiers in Bioscience-Elite · doi:10.2741/541 · Cited by 51
“5 defective vascular remodelling in yolk sac and embryo (234)”
BackgroundHypoxia-Dependent Angiogenesis and Lymphangiogenesis in Cancer
Schito, L. (2019) · Advances in experimental medicine and biology · doi:10.1007/978-3-030-12734-3_5 · Cited by 93
From Vessel Sprouting to Normalization
Coulon, C., Γεωργιάδου, Μ., Roncal, C., Bock, K. D., Langenberg, T., & Carmeliet, P. (2010) · Arteriosclerosis Thrombosis and Vascular Biology · doi:10.1161/atvbaha.110.214106 · Cited by 72
Lu, B., Zagouras, P., Fischer, J. E., Lu, J. F., Li, B., & Flavell, R. A. (2004) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0307743100 · Cited by 54
Renal anemia: from incurable to curable
Sato, Y., & Yanagita, M. (2013) · American Journal of Physiology-Renal Physiology · doi:10.1152/ajprenal.00233.2013 · Cited by 62
“Since HIF-1 and HIF-2 knockout mice are embryonic lethal (99), Gruber and colleagues (41) developed a mouse model with inducible inactivation of HIF- using the tamoxifen-CreERT2 system and investigated the physiological role of HIF-1 and HIF-2 in the adult (41).”
MethodEffects of curcumin on hypoxia-inducible factor as a new therapeutic target
Bahrami, A., Atkin, S. L., Majeed, M. A., & Sahebkar, A. (2018) · Pharmacological Research · doi:10.1016/j.phrs.2018.10.009 · Cited by 65
“However, many tumor cells have amplified HIF-2α mRNA that is comparable to HIF-1α regarding protein structure and regulation [141,142].”
BackgroundInvolvement of vessels and PDGFB in muscle splitting during chick limb development
Tozer, S., Bonnin, M.-A., Relaix, F., Savino, S. D., García‐Villalba, P., Coumailleau, P., & Duprez, D. (2007) · Development · doi:10.1242/dev.02867 · Cited by 70
“We analyzed the blood vessel pattern in the absence of muscle cells using two mouse vascular markers, PECAM1 and the bHLH-PAS transcription factor gene Hif2 (Epas1 – Mouse Genome Informatics) (Peng et al., 2000).”
MethodPietras, A., Johnsson, A. S., & Påhlman, S. (2010) · Current topics in microbiology and immunology · doi:10.1007/82_2010_72 · Cited by 62
“Despite displaying incompletely overlapping phenotypes, four different Hif2a knockout mice have been instrumental in identifying putative roles for HIF2A during normal development (Tian et al. 1998; Peng et al. 2000; Compernolle et al. 2002; Scortegagna et al. 2003).”
InfluentialFurness, S. G. B., & Whelan, F. (2009) · Pharmacology & Therapeutics · doi:10.1016/j.pharmthera.2009.09.004 · Cited by 63
Hypoxia-Inducible Factors as an Alternative Source of Treatment Strategy for Cancer
Akanji, M. A., Rotimi, D. E., & Adeyemı, O. S. (2019) · Oxidative Medicine and Cellular Longevity · doi:10.1155/2019/8547846 · Cited by 78
“With different clinical and experimental research establishing HIF as a cancer therapy target, HIF-1α and HIF-2α levels are associated with metastasis, vascularization, and tumor growth in both animal-based and clinical-based studies.”
BackgroundInfluentialActivation of the VEGFR1 Chromatin Domain
Dutta, D., Ray, S. S., Vivian, J. L., & Paul, S. (2008) · Journal of Biological Chemistry · doi:10.1074/jbc.m804349200 · Cited by 58
Metadata
- Authors
- Peng, J., Zhang, L., Drysdale, L., & Fong, G.-H.
- Affiliations
- Western University (CA)
- 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
- 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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