title: Non-endothelial cell endothelin-B receptors limit neointima formation following vascular injury.
abstract: OBJECTIVE
  The potent vasoconstrictor endothelin-1 (ET-1), acting on the endothelin-A (ETA) receptor, promotes intimal lesion formation following vascular injury. The endothelin-B (ETB) receptor, which mediates nitric oxide release and ET-1 clearance in endothelial cells, may moderate lesion formation, but this is less clear. We used selective ET receptor antagonists and cell-specific deletion to address the hypothesis that ETB receptors in the endothelium inhibit lesion formation following arterial injury.
  
  
  RESULTS
  Neointimal proliferation was induced by wire or ligation injury to the femoral artery in mice treated with selective ETA (ABT-627) and/or ETB antagonists (A192621). Measurement of lesion formation by optical projection tomography and histology indicated that ETA blockade reduced lesion burden in both models. Although ETB blockade had little effect on ligation injury-induced lesion formation, after wire injury, blockade of the ETB receptor increased lesion burden (184% of vehicle; P < 0.05) and reversed the protective effects of an ETA antagonist. Selective deletion of ETB receptors from the endothelium, however, had no effect on neointimal lesion size.
  
  
  CONCLUSIONS
  These results are consistent with ETB receptor activation playing an important role in limiting neointimal lesion formation following acute vascular injury, but indicate that this protective effect is not mediated by those ETB receptors expressed by endothelial cells. These data support the proposal that selective ETA antagonists may be preferable to mixed ETA/ETB antagonists for targeting the arterial response to injury.
authors.affiliation: Centre for Cardiovascular Science, The Queen's Medical Research Institute, University of Edinburgh, Edinburgh, UK.
authors.forename: Nicholas S
authors.initials: NS
authors.lastname: Kirkby
authors.forename: Karolina M
authors.initials: KM
authors.lastname: Duthie
authors.forename: Eileen
authors.initials: E
authors.lastname: Miller
authors.forename: Yuri V
authors.initials: YV
authors.lastname: Kotelevtsev
authors.forename: Alan J
authors.initials: AJ
authors.lastname: Bagnall
authors.forename: David J
authors.initials: DJ
authors.lastname: Webb
authors.forename: Patrick W F
authors.initials: PW
authors.lastname: Hadoke
mesh_terms: D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D065131:Endothelin B Receptor Antagonists; D019332:Endothelin-1 / Q000494:pharmacology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D058426:Neointima / Q000517:prevention & control*; D011759:Pyrrolidines / Q000494:pharmacology; D044022:Receptor, Endothelin A / Q000502:physiology; D044023:Receptor, Endothelin B / Q000502:physiology*; D057772:Vascular System Injuries / Q000473:pathology*
chemical_list: C120508:A 192621; D065131:Endothelin B Receptor Antagonists; D019332:Endothelin-1; D011759:Pyrrolidines; D044022:Receptor, Endothelin A; D044023:Receptor, Endothelin B