title: Plaque-associated endothelial dysfunction in apolipoprotein E-deficient mice on a regular diet. Effect of human apolipoprotein AI.
abstract: OBJECTIVE
  Apolipoprotein E-deficient mice (apoE(-/-)) on a regular diet become hypercholesterolemic and develop atherosclerosis, but endothelium-dependent relaxation remains undisturbed for up to 6 months. We investigated whether vasomotor dysfunction develops in aged apoE(-/-), whether the defect was systemic (hypercholesterolemia-dependent) or focal (plaque-related), and the effect of human apolipoprotein AI transgenesis (apoAI/E(-/-)).
  
  
  METHODS
  Arteries of apoE(-/-) (n=5), apoAI/E(-/-) (n=6) and C57Bl/6J (WT, n=4) mice (18 months) were systematically dissected for isometric tension recording and subsequent morphometry.
  
  
  RESULTS
  Acetylcholine (ACh)-induced relaxation was impaired (P<0.01) in atherosclerotic segments of apoE(-/-) (26+/-14%) as compared to WT mice (93+/-2%). Similar reduced (P<0.01) responses to adenosine 5'-triphosphate (apoE(-/-) 38+/-14, WT 94+/-3%) and the calcium ionophore A23187 (apoE(-/-) 19+/-6%, WT 97+/-2%) pointed to a post-receptor defect. Indeed, responses to exogenous nitric oxide were impaired in atherosclerotic segments as well (apoE(-/-) 71+/-7%, WT 92+/-1%, P<0.05). Furthermore, relaxations inversely correlated with plaque size (ACh r(s)=-0.74, P<0.01). In adjacent plaque-free segments however, responses to ACh (apoE(-/-) 92+/-3%, WT 97+/-1%) and all other agents were preserved, despite the prolonged hypercholesterolemia. ApoAI improved vasomotor responses in atherosclerotic segments. However, negative correlations between maximal relaxation and plaque area remained in apoAI/E(-/-) mice (ACh r(s)=-0.67, P<0.01). Indeed, covariate analysis of variance did not point to direct protection of vasomotor function by apoAI when the smaller lesions were taken into account.
  
  
  CONCLUSIONS
  Endothelial dysfunction in apoE(-/-) mice is not affected by hypercholesterolemia alone, but is strictly associated with plaque formation. Human apoAI transgenesis-known to raise HDL-attenuated atherogenesis, thereby indirectly improving relaxation responses in apoE(-/-) mice.
authors.affiliation: Division of Pharmacology (T2), University of Antwerp, Universiteitsplein 1, B-2610 Wilrijk, Belgium. herta.crauwels@ua.ac.be
authors.forename: Herta M
authors.initials: HM
authors.lastname: Crauwels
authors.forename: Cor E
authors.initials: CE
authors.lastname: Van Hove
authors.forename: Paul
authors.initials: P
authors.lastname: Holvoet
authors.forename: Arnold G
authors.initials: AG
authors.lastname: Herman
authors.forename: Hidde
authors.initials: H
authors.lastname: Bult
mesh_terms: D000818:Animals; D001013:Aorta, Thoracic; D016632:Apolipoprotein A-I / Q000235:genetics*; D001057:Apolipoproteins E / Q000172:deficiency*; D001161:Arteriosclerosis / Q000378:metabolism* / Q000473:pathology; D002339:Carotid Arteries; D002784:Cholesterol / Q000097:blood; D004305:Dose-Response Relationship, Drug; D004730:Endothelium, Vascular / Q000378:metabolism*; D006801:Humans; D007009:Hypolipoproteinemias / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D010656:Phenylephrine / Q000494:pharmacology; D014662:Vasoconstrictor Agents / Q000494:pharmacology
chemical_list: D016632:Apolipoprotein A-I; D001057:Apolipoproteins E; D014662:Vasoconstrictor Agents; D010656:Phenylephrine; D002784:Cholesterol