Coordinated Adenine Nucleotide Phosphohydrolysis and Nucleoside Signaling in Posthypoxic Endothelium
Open accessAbstract
Limited oxygen delivery to tissues (hypoxia) is common in a variety of disease states. A number of parallels exist between hypoxia and acute inflammation, including the observation that both influence vascular permeability. As such, we compared the functional influence of activated polymorphonuclear leukocytes (PMN) on normoxic and posthypoxic endothelial cells. Initial studies indicated that activated PMN preferentially promote endothelial barrier function in posthypoxic endothelial cells (>60% increase over normoxia). Extension of these findings identified at least one soluble mediator as extracellular adenosine triphosphate (ATP). Subsequent studies revealed that ATP is coordinately hydrolyzed to adenosine at the endothelial cell surface by hypoxia-induced CD39 and CD73 (>20-and >12-fold increase in mRNA, respectively). Studies in vitro and in cd39-null mice identified these surface ecto-enzymes as critical control points for posthypoxia-associated protection of vascular permeability. Furthermore, insight gained through microarray analysis revealed that the adenosine A2B receptor (AdoRA2B) is selectively up-regulated by hypoxia (>5-fold increase in mRNA), and that AdoRA2B antagonists effectively neutralize ATP-mediated changes in posthypoxic endothelial permeability. Taken together, these results demonstrate transcription coordination of adenine nucleotide and nucleoside signaling at the vascular interface during hypoxia.
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Amelioration of disease occurs, at least in part, through transcriptional up-regulation of non-classical epithelial barrier genes.
“Amelioration of disease occurs, at least in part, through transcriptional up-regulation of non-classical epithelial barrier genes.”
From Hypoxia: an alarm signal during intestinal inflammation (2010) · cites this paper as [22]
HIF-1 triggers the transcription of many genes that enable intestinal epithelial cells to act as an effective barrier.
“Several studies have shown that HIF-1 triggers the transcription of many genes that enable intestinal epithelial cells to act as an effective barrier4,20–22.”
From Hypoxia: an alarm signal during intestinal inflammation (2010) · cites this paper as [22]
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- Authors
- Eltzschig, H. K., Ibla, J. C., Furuta, G. T., Leonard, M. O., Jacobson, K. A., Enjyoji, K., Robson, S. C., & Colgan, S. P.
- Affiliations
- Brigham and Women's Hospital (US)
- 2Department of Anesthesiology, Perioperative and Pain Medicine
- Harvard University (US)
- University College Dublin (IE)
- National Institutes of Health (US)
- Beth Israel Deaconess Medical Center (US)
- ORCID
- Venue
- The Journal of Experimental Medicine
- Publisher
- Rockefeller University Press
- Published
- 2003-08-25
- Volume
- 198
- Issue
- 5
- Pages
- 783-796
- ISSN
- 0022-1007 (ISSN-L)
- 1540-9538
- PMC
- PMC2194189
- OpenAlex
- W2138216041
- Cited by
- 499
- References
- 48
- Citations by year
- 2026: 8 · 2025: 9 · 2024: 18 · 2023: 19 · 2022: 18 · 2021: 8 · 2020: 14 · 2019: 21 · 2018: 18 · 2017: 20 · 2016: 21 · 2015: 23 · 2014: 18 · 2013: 37 · 2012: 37
- FWCI
- 8.80
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- cc-by-nc-sa
- Locations
- The Journal of Experimental Medicine (publishedVersion)
- PubMed Central (publishedVersion, cc-by-nc-sa)
- PubMed (publishedVersion)
- Funders
- National Institutes of Health (DE13499, DK-50189, HL60569)
- National Heart, Lung, and Blood Institute (R01HL060569, HL-60569)
- National Institute of Diabetes and Digestive and Kidney Diseases (Z01DK031116, R01DK050189, R37DK050189, R29DK050189, DK-50189)
- National Institute of Dental and Craniofacial Research (DE13499, P01DE013499)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Physiology › Adenosine and Purinergic Signaling
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Biochemical and Molecular Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Angiogenesis and VEGF in Cancer
- Keywords
- hypoxia, endothelial barrier function, vascular permeability, polymorphonuclear leukocytes, extracellular ATP, adenosine triphosphate hydrolysis, CD39, CD73, adenosine A2B receptor, inflammation, transcriptional regulation
- MeSH terms
- Adenine Nucleotides, Adenosine, Adenosine Triphosphatases, Apyrase, Base Sequence, Cell Membrane Permeability, Cells, Cultured, Endothelium, Vascular, Humans, Hydrolysis, Kinetics, Microcirculation, Neutrophils, Oxygen Consumption, Pyrophosphatases, Signal Transduction, Cell Hypoxia, Antigens, CD, Up-Regulation, DNA Primers, Receptors, Purinergic P1, Neutrophil Activation, Receptor, Adenosine A2B
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