title: Vascular endothelin-B receptor system in vivo plays a favorable inhibitory role in vascular remodeling after injury revealed by endothelin-B receptor-knockout mice.
abstract: BACKGROUND
  Two subtypes of endothelin (ET) receptors, ET(A) and ET(B), are distributed in vascular smooth muscle cells to cause contraction and proliferation. Vascular endothelial cells express only ET(B) receptors, which cause NO release. Although ET(A) receptor blockade is reported to be effective in ameliorating vascular remodeling, there is no report on the long-term effect of ET(B) receptor blockade on vascular remodeling after injury.
  
  
  RESULTS
  ET(B) receptor-knockout (KO) mice, which were genetically rescued from lethal intestinal aganglionosis, and wild-type (WT) mice underwent complete ligation of the right common carotid artery, ie, a blood flow cessation model of vascular remodeling. Fourteen days after ligation, the intimal area, the ratio of intimal to medial areas, and the stenotic ratio in the ligated artery of KO mice were significantly increased compared with those of WT mice. The expression level of ET-1 mRNA in the ligated artery of KO mice was increased similarly to that of WT mice, whereas tissue NO(x) levels in lesions of KO mice were significantly lower than those of WT mice. Long-term treatment with the ET(A) receptor antagonist TA-0201 (0.5 mg x kg(-1) x d(-1)) significantly ameliorated vascular stenosis in both groups. Long-term treatment with the ET(B) receptor antagonist A-192621 (30 mg x kg(-1) x d(-1)) worsened vascular remodeling in WT mice.
  
  
  CONCLUSIONS
  We demonstrated that inhibition of the ET(B) receptor system is harmful for vascular remodeling after injury, the mechanism of which is partly attributed to decreased NO release, in KO mice. These results suggest that the overall effect of vascular ET(B) receptors is antiproliferative in the injured artery.
authors.affiliation: Cardiovascular Division, Department of Internal Medicine, Institute of Clinical Medicine, University of Tsukuba, Ibaraki, Japan.
authors.forename: Nobuyuki
authors.initials: N
authors.lastname: Murakoshi
authors.forename: Takashi
authors.initials: T
authors.lastname: Miyauchi
authors.forename: Yoshihiko
authors.initials: Y
authors.lastname: Kakinuma
authors.forename: Takashi
authors.initials: T
authors.lastname: Ohuchi
authors.forename: Katsutoshi
authors.initials: K
authors.lastname: Goto
authors.forename: Masashi
authors.initials: M
authors.lastname: Yanagisawa
authors.forename: Iwao
authors.initials: I
authors.lastname: Yamaguchi
mesh_terms: D000818:Animals; D001157:Arterial Occlusive Diseases / Q000209:etiology* / Q000378:metabolism / Q000473:pathology; D017536:Carotid Artery, Common / Q000378:metabolism / Q000473:pathology / Q000601:surgery; D065128:Endothelin Receptor Antagonists; D019332:Endothelin-1 / Q000096:biosynthesis / Q000235:genetics; D004730:Endothelium, Vascular / Q000378:metabolism; D008026:Ligation; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009569:Nitric Oxide / Q000032:analysis; D011743:Pyrimidines / Q000008:administration & dosage / Q000494:pharmacology; D011759:Pyrrolidines / Q000494:pharmacology; D012333:RNA, Messenger / Q000096:biosynthesis; D044022:Receptor, Endothelin A; D044023:Receptor, Endothelin B; D017466:Receptors, Endothelin / Q000235:genetics / Q000502:physiology*; D013449:Sulfonamides / Q000008:administration & dosage / Q000494:pharmacology
chemical_list: C120508:A 192621; D065128:Endothelin Receptor Antagonists; D019332:Endothelin-1; D011743:Pyrimidines; D011759:Pyrrolidines; D012333:RNA, Messenger; D044022:Receptor, Endothelin A; D044023:Receptor, Endothelin B; D017466:Receptors, Endothelin; D013449:Sulfonamides; C113972:T 0201; D009569:Nitric Oxide