title: Endothelin ETA receptors predominate in chronic thromboembolic pulmonary hypertension.
abstract: OBJECTIVE
  Endothelin-1 levels are raised in chronic thromboembolic pulmonary hypertension. Our aim in this study was to identify the presence of endothelin receptors in patients with CTEPH by analysing tissue removed at pulmonary endarterectomy.
  
  
  METHODS
  Pulmonary endarterectomy tissue cross-sections were analysed using autoradiography with [(125)I]-ET-1 using ligands selective for ETA or ETB to determine sub-type distribution. The precise cellular localisation of ETA and ETB receptors was determined using selective antisera to both sub-types and compared with haematoxylin and eosin, Elastic Van Gieson and smooth muscle actin labelled sections.
  
  
  RESULTS
  Two patterns of ET-1 binding were found. In sections with frequent recanalised channels, ET-1 bound to the smooth muscle cells surrounding the channels. In sections where there was less organised thrombus with no obvious re-canalisation, minimal ET-1 binding was observed. Some contractile type smooth muscle cells not associated with recanalised channels and diffusely spread throughout the PEA material were associated with ET receptor antibody binding on immunohistochemistry. There was a greater expression of the ETA receptor type in the specimens.
  
  
  CONCLUSIONS
  The presence of ET-1 receptors in the chronic thrombus in proximal CTEPH suggests ET-1 could act not only on the distal vasculopathy in the unobstructed vessels but may also stimulate smooth muscle cell proliferation within chronic clot. The abundance of ET receptors within the tissue provides evidence that the ET pathway is involved in the pathology of chronic thrombus reorganisation leading to CTEPH providing a rationale for the repurposing of ET receptor antagonists in the treatment of this condition.
authors.affiliation: Papworth Hospital, Cambridge, UK,; Experimental Medicine and Therapeutics, University of Cambridge, Cambridge, UK.
authors.forename: Mark
authors.initials: M
authors.lastname: Southwood
authors.affiliation: Royal United Hospitals, Bath, UK.
authors.forename: Robert V
authors.initials: RV
authors.lastname: MacKenzie Ross
authors.affiliation: Experimental Medicine and Therapeutics, University of Cambridge, Cambridge, UK.
authors.forename: Rhoda E
authors.initials: RE
authors.lastname: Kuc
authors.affiliation: Papworth Hospital, Cambridge, UK.
authors.forename: Guy
authors.initials: G
authors.lastname: Hagan
authors.affiliation: Papworth Hospital, Cambridge, UK.
authors.forename: Karen K
authors.initials: KK
authors.lastname: Sheares
authors.affiliation: Papworth Hospital, Cambridge, UK.
authors.forename: David P
authors.initials: DP
authors.lastname: Jenkins
authors.affiliation: Papworth Hospital, Cambridge, UK.
authors.forename: Martin
authors.initials: M
authors.lastname: Goddard
authors.affiliation: Experimental Medicine and Therapeutics, University of Cambridge, Cambridge, UK. Electronic address: apd10@medschl.cam.ac.uk.
authors.forename: Anthony P
authors.initials: AP
authors.lastname: Davenport
authors.affiliation: Papworth Hospital, Cambridge, UK.
authors.forename: Joanna
authors.initials: J
authors.lastname: Pepke-Zaba
mesh_terms: D001345:Autoradiography; D002908:Chronic Disease; D065128:Endothelin Receptor Antagonists / Q000627:therapeutic use; D006801:Humans; D006976:Hypertension, Pulmonary / Q000150:complications / Q000188:drug therapy / Q000378:metabolism*; D018613:Microscopy, Confocal; D011485:Protein Binding; D044022:Receptor, Endothelin A / Q000378:metabolism*; D013923:Thromboembolism / Q000150:complications / Q000188:drug therapy / Q000378:metabolism*
chemical_list: D065128:Endothelin Receptor Antagonists; D044022:Receptor, Endothelin A
keywords: Autoradiography; Chronic thromboembolic pulmonary hypertension; Endothelin-1; Immunocytochemistry; Pulmonary endarterectomy