title: Endothelial Expression of Endothelin Receptor A in the Systemic Capillary Leak Syndrome.
abstract: 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.
authors.affiliation: National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, United States of America.
authors.forename: Albert C
authors.initials: AC
authors.lastname: Sek
authors.affiliation: National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, United States of America.
authors.forename: Zhihui
authors.initials: Z
authors.lastname: Xie
authors.affiliation: Division of Hematology/Oncology, Department of Medicine, University of Illinois at Chicago, Chicago, IL, United States of America.
authors.forename: Kaoru
authors.initials: K
authors.lastname: Terai
authors.affiliation: National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, United States of America.
authors.forename: Lauren M
authors.initials: LM
authors.lastname: Long
authors.affiliation: National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, United States of America.
authors.forename: Celeste
authors.initials: C
authors.lastname: Nelson
authors.affiliation: Division of Hematology/Oncology, Department of Medicine, University of Illinois at Chicago, Chicago, IL, United States of America.
authors.forename: Arkadiusz Z
authors.initials: AZ
authors.lastname: Dudek
authors.affiliation: National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, United States of America.
authors.forename: Kirk M
authors.initials: KM
authors.lastname: Druey
mesh_terms: D020013:Calcium Signaling / Q000187:drug effects / Q000235:genetics; D019559:Capillary Leak Syndrome / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D016022:Case-Control Studies; D002460:Cell Line; D002463:Cell Membrane Permeability / Q000187:drug effects; D054357:Chemokine CXCL10 / Q000494:pharmacology; D042783:Endothelial Cells / Q000187:drug effects / Q000378:metabolism; D019332:Endothelin-1 / Q000378:metabolism; D004730:Endothelium, Vascular / Q000187:drug effects / Q000378:metabolism*; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D018836:Inflammation Mediators / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D044022:Receptor, Endothelin A / Q000235:genetics / Q000378:metabolism*
chemical_list: D054357:Chemokine CXCL10; D019332:Endothelin-1; D018836:Inflammation Mediators; D044022:Receptor, Endothelin A