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Endothelial Expression of Endothelin Receptor A in the Systemic Capillary Leak Syndrome
Idiopathic systemic capillary leak syndrome (SCLS) is a rare and potentially fatal vascular disorder characterized by reversible bouts of hypotension and edema resulting from fluid and solute escape into soft tissues. Although spikes in permeability-inducing factors have been linked to acute SCLS fl...
Autores principales: | , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
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Public Library of Science
2015
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4503617/ https://www.ncbi.nlm.nih.gov/pubmed/26176954 http://dx.doi.org/10.1371/journal.pone.0133266 |
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author | Sek, Albert C. Xie, Zhihui Terai, Kaoru Long, Lauren M. Nelson, Celeste Dudek, Arkadiusz Z. Druey, Kirk M. |
author_facet | Sek, Albert C. Xie, Zhihui Terai, Kaoru Long, Lauren M. Nelson, Celeste Dudek, Arkadiusz Z. Druey, Kirk M. |
author_sort | Sek, Albert C. |
collection | PubMed |
description | Idiopathic systemic capillary leak syndrome (SCLS) is a rare and potentially fatal vascular disorder characterized by reversible bouts of hypotension and edema resulting from fluid and solute escape into soft tissues. Although spikes in permeability-inducing factors have been linked to acute SCLS flares, whether or not they act on an inherently dysfunctional endothelium is unknown. To assess the contribution of endothelial-intrinsic mechanisms in SCLS, we derived blood-outgrowth endothelial cells (BOEC) from patients and healthy controls and examined gene expression patterns. Ednra, encoding Endothelin receptor A (ETA)—the target of Endothelin 1 (ET-1)—was significantly increased in SCLS BOEC compared to healthy controls. Although vasoconstriction mediated by ET-1 through ETA activation on vascular smooth muscle cells has been well characterized, the expression and function of ETA receptors in endothelial cells (ECs) has not been described. To determine the role of ETA and its ligand ET-1 in SCLS, if any, we examined ET-1 levels in SCLS sera and functional effects of endothelial ETA expression. ETA overexpression in EAhy926 endothelioma cells led to ET-1-induced hyper-permeability through canonical mechanisms. Serum ET-1 levels were elevated in acute SCLS sera compared to remission and healthy control sera, suggesting a possible role for ET-1 and ETA in SCLS pathogenesis. However, although ET-1 alone did not induce hyper-permeability of patient-derived BOEC, an SCLS-related mediator (CXCL10) increased Edrna quantities in BOEC, suggesting a link between SCLS and endothelial ETA expression. These results demonstrate that ET-1 triggers classical mechanisms of vascular barrier dysfunction in ECs through ETA. Further studies of the ET-1-ETA axis in SCLS and in more common plasma leakage syndromes including sepsis and filovirus infection would advance our understanding of vascular integrity mechanisms and potentially uncover new treatment strategies. |
format | Online Article Text |
id | pubmed-4503617 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2015 |
publisher | Public Library of Science |
record_format | MEDLINE/PubMed |
spelling | pubmed-45036172015-07-17 Endothelial Expression of Endothelin Receptor A in the Systemic Capillary Leak Syndrome Sek, Albert C. Xie, Zhihui Terai, Kaoru Long, Lauren M. Nelson, Celeste Dudek, Arkadiusz Z. Druey, Kirk M. PLoS One Research Article Idiopathic systemic capillary leak syndrome (SCLS) is a rare and potentially fatal vascular disorder characterized by reversible bouts of hypotension and edema resulting from fluid and solute escape into soft tissues. Although spikes in permeability-inducing factors have been linked to acute SCLS flares, whether or not they act on an inherently dysfunctional endothelium is unknown. To assess the contribution of endothelial-intrinsic mechanisms in SCLS, we derived blood-outgrowth endothelial cells (BOEC) from patients and healthy controls and examined gene expression patterns. Ednra, encoding Endothelin receptor A (ETA)—the target of Endothelin 1 (ET-1)—was significantly increased in SCLS BOEC compared to healthy controls. Although vasoconstriction mediated by ET-1 through ETA activation on vascular smooth muscle cells has been well characterized, the expression and function of ETA receptors in endothelial cells (ECs) has not been described. To determine the role of ETA and its ligand ET-1 in SCLS, if any, we examined ET-1 levels in SCLS sera and functional effects of endothelial ETA expression. ETA overexpression in EAhy926 endothelioma cells led to ET-1-induced hyper-permeability through canonical mechanisms. Serum ET-1 levels were elevated in acute SCLS sera compared to remission and healthy control sera, suggesting a possible role for ET-1 and ETA in SCLS pathogenesis. However, although ET-1 alone did not induce hyper-permeability of patient-derived BOEC, an SCLS-related mediator (CXCL10) increased Edrna quantities in BOEC, suggesting a link between SCLS and endothelial ETA expression. These results demonstrate that ET-1 triggers classical mechanisms of vascular barrier dysfunction in ECs through ETA. Further studies of the ET-1-ETA axis in SCLS and in more common plasma leakage syndromes including sepsis and filovirus infection would advance our understanding of vascular integrity mechanisms and potentially uncover new treatment strategies. Public Library of Science 2015-07-15 /pmc/articles/PMC4503617/ /pubmed/26176954 http://dx.doi.org/10.1371/journal.pone.0133266 Text en https://creativecommons.org/publicdomain/zero/1.0/ This is an open-access article distributed under the terms of the Creative Commons Public Domain declaration, which stipulates that, once placed in the public domain, this work may be freely reproduced, distributed, transmitted, modified, built upon, or otherwise used by anyone for any lawful purpose. |
spellingShingle | Research Article Sek, Albert C. Xie, Zhihui Terai, Kaoru Long, Lauren M. Nelson, Celeste Dudek, Arkadiusz Z. Druey, Kirk M. Endothelial Expression of Endothelin Receptor A in the Systemic Capillary Leak Syndrome |
title | Endothelial Expression of Endothelin Receptor A in the Systemic Capillary Leak Syndrome |
title_full | Endothelial Expression of Endothelin Receptor A in the Systemic Capillary Leak Syndrome |
title_fullStr | Endothelial Expression of Endothelin Receptor A in the Systemic Capillary Leak Syndrome |
title_full_unstemmed | Endothelial Expression of Endothelin Receptor A in the Systemic Capillary Leak Syndrome |
title_short | Endothelial Expression of Endothelin Receptor A in the Systemic Capillary Leak Syndrome |
title_sort | endothelial expression of endothelin receptor a in the systemic capillary leak syndrome |
topic | Research Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4503617/ https://www.ncbi.nlm.nih.gov/pubmed/26176954 http://dx.doi.org/10.1371/journal.pone.0133266 |
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