title: Reduced cyclooxygenase involvement in vascular endothelial function in rat renal transplantation.
abstract: BACKGROUND
  Cardiovascular disease is a major cause of death following renal transplantation. Mechanisms leading to vascular dysfunction outside the transplanted organ involve common risk factors such as hypertension, hypercholesterolemia, proteinuria, but immune-mediated factors may also be involved. We hypothesized that transplantation-associated risk factors are involved in the development of vascular dysfunction following renal transplantation.
  
  
  METHODS
  Vascular function was studied in Fisher to Lewis allografts. Lewis to Lewis syngrafted rats served as controls. All rats received cyclosporin A for 10 days. Allografts were treated with ACE inhibition or AT1 receptor blockade or left untreated. After 34 weeks, aorta rings were studied for contractile and dilator responses in the presence or absence of L-NMMA and/or indomethacin. Tissue sections were immunostained for COX-1 and COX-2.
  
  
  RESULTS
  In contrast to syngrafts and treated allografts, untreated allografts developed proteinuria and hypercholesterolemia. In aortic rings, NOS inhibition similarly increased contractile responses and decreased dilator responses in syngrafts and allografts, indicating comparable NO pathways. In contrast, indomethacin affected contractile and dilator responses in syngrafts, but not in treated and untreated allografts, indicating absence of COX-derived prostanoids in control over vascular tone in allografts. This was in line with immunohistologic analysis demonstrating reduced aortic COX-2 expression in allografts. COX-1 expression was unaltered. Interestingly, RAS blockade quantitatively increased endothelium-dependent dilation without qualitatively altering COX function and expression.
  
  
  CONCLUSIONS
  Involvement of COX-derived prostaglandins in vascular endothelial function outside the transplanted organ is strongly diminished after allogeneic renal transplantation. RAS blockade improves common cardiovascular risk factors and endothelium-dependent dilation, but fails to restore prostaglandin function.
authors.affiliation: Department of Pathology and Laboratory Medicine, University Hospital Groningen, Groningen, The Netherlands. a.smit-van.oosten@med.umcg.nl
authors.forename: Annemieke
authors.initials: A
authors.lastname: Smit-van Oosten
authors.forename: Arnold H
authors.initials: AH
authors.lastname: Boonstra
authors.forename: Gerjan
authors.initials: G
authors.lastname: Navis
authors.forename: Harry
authors.initials: H
authors.lastname: van Goor
authors.forename: Hendrik
authors.initials: H
authors.lastname: Buikema
mesh_terms: D000818:Animals; D001011:Aorta / Q000502:physiology*; D051545:Cyclooxygenase 1 / Q000378:metabolism*; D051546:Cyclooxygenase 2 / Q000378:metabolism*; D004730:Endothelium, Vascular / Q000502:physiology*; D016030:Kidney Transplantation / Q000502:physiology*; D008297:Male; D008565:Membrane Proteins / Q000378:metabolism*; D009569:Nitric Oxide / Q000378:metabolism*; D019001:Nitric Oxide Synthase / Q000378:metabolism; D051381:Rats; D011916:Rats, Inbred F344; D011917:Rats, Inbred Lew; D014661:Vasoconstriction / Q000502:physiology; D014664:Vasodilation / Q000502:physiology
chemical_list: D008565:Membrane Proteins; D009569:Nitric Oxide; D019001:Nitric Oxide Synthase; D051545:Cyclooxygenase 1; D051546:Cyclooxygenase 2; C496513:Ptgs1 protein, rat; C489691:Ptgs2 protein, rat