The hypoxia-responsive transcription factor EPAS1 is essential for catecholamine homeostasis and protection against heart failure during embryonic development
Open accessAbstract
Mice lacking the hypoxia-inducible transcription factor EPAS1 die at mid-gestation. Despite normal morphological development of the circulatory system, EPAS1-deficient mice display pronounced bradycardia. In addition to the vascular endothelium, EPAS1 is expressed intensively in the organ of Zuckerkandl (OZ), the principle source of catecholamine production in mammalian embryos. EPAS1-deficient embryos contained substantially reduced catecholamine levels. Mid-gestational lethality was rescued by administration of the catecholamine precursor DOPS to pregnant females. We hypothesize that EPAS1 expressed in the OZ senses hypoxia during mid-gestational development and translates this signal into an altered pattern of gene expression, leading to increases in circulating catecholamine levels and proper cardiac function.
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HIF-2α is transiently and specifically expressed in human embryonal and fetal SNS cells and during rodent SNS development.
“HIF-2α is transiently and specifically expressed in human embryonal and fetal SNS cells and during rodent SNS development (Tian et al., 1998;Nilsson et al., 2005;Mohlin et al., 2013).”
From Therapeutic targeting of hypoxia and hypoxia-inducible factors in cancer (2016) · cites this paper as Tian et al., 1998
The paper’s expression analysis (Fig. 3; page unavailable in our copy) shows EPAS1 in the mouse sympathetic chain at E11.5, down-regulation there by E12.5, and expression in the developing organ of Zuckerkandl. This supports transient expression during rodent sympathoadrenal development, but the paper does not establish expression in human embryonal or fetal SNS cells, and its reported expression is not specific to SNS cells. (LLM, conf=0.89)
Experimental — accuracy not yet measuredMouse embryos lacking HIF-2α have severely reduced norepinephrine levels compared to wild type mice.
“Consistent with these observations, mouse embryos lacking HIF-2α have severely reduced norepinephrine levels compared to wild type mice (Tian et al., 1998).”
From Therapeutic targeting of hypoxia and hypoxia-inducible factors in cancer (2016) · cites this paper as Tian et al., 1998
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- Authors
- Tian, H., Hammer, R. E., Matsumoto, A. M., Russell, D. W., & McKnight, S. L.
- Affiliations
- Howard Hughes Medical Institute (US)
- Venue
- Genes & Development
- Publisher
- Cold Spring Harbor Laboratory
- Published
- 1998-11-01
- Volume
- 12
- Issue
- 21
- Pages
- 3320-3324
- ISSN
- 0890-9369 (ISSN-L)
- 1549-5477
- PMC
- PMC317225
- OpenAlex
- W2120657231
- Cited by
- 647
- References
- 3
- Citations by year
- 2026: 8 · 2025: 17 · 2024: 13 · 2023: 13 · 2022: 12 · 2021: 18 · 2020: 19 · 2019: 16 · 2018: 15 · 2017: 15 · 2016: 18 · 2015: 25 · 2014: 28 · 2013: 26 · 2012: 17
- Type
- posted content
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Genes & Development (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institutes of Health (5p50dk047657-10, DK47657)
- National Institute of Diabetes and Digestive and Kidney Diseases (DK52031, DK 47657)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Congenital heart defects research
- Life Sciences › Neuroscience › Endocrine and Autonomic Systems › Neuroscience of respiration and sleep
- Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Pulmonary Hypertension Research and Treatments
- Keywords
- EPAS1, hypoxia-inducible factor, heart failure, embryonic development, organ of Zuckerkandl, bradycardia, DOPS, catecholamine precursors, hypoxia sensing, cardiac function
- MeSH terms
- Endothelial PAS Domain-Containing Protein 1, Animals, Catecholamines, Embryonic and Fetal Development, Heart Failure, Homeostasis, Male, Mice, Inbred C57BL, Mice, Transgenic, Mutation, Phenotype, Trans-Activators, Helix-Loop-Helix Motifs, Mice, Basic Helix-Loop-Helix Proteins, Basic Helix-Loop-Helix Transcription Factors
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