© 2003 by European Society of Cardiology
Copyright © 2003, European Society of Cardiology
Plaque-associated endothelial dysfunction in apolipoprotein E-deficient mice on a regular diet. Effect of human apolipoprotein AI
aDivision of Pharmacology (T2), University of Antwerp (UIA), Universiteitsplein 1, B-2610 Wilrijk, Belgium
bCentre for Experimental Surgery and Anaesthesiology, University of Leuven (KUL), Leuven, Belgium
herta.crauwels{at}ua.ac.be
* Corresponding author. Tel.: +32-3-820-2737; fax: +32-3-820-2567.
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 [GenBank] (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 rs=–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 rs=–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.
KEYWORDS Atherosclerosis; Nitric oxide; Endothelial function; Vasodilation; Histopathology; Hypercholesterolemia; apoAI; HDL
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