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Abstract no.: 5
Endothelium‐dependent relaxation and impact of a Western type diet in the aorta of apolipoprotein E‐deficient mice
Author(s) -
Crauwels H.M.,
Hove C.E.,
Herman A.G.,
Bult H.
Publication year - 2005
Publication title -
fundamental and clinical pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.655
H-Index - 73
eISSN - 1472-8206
pISSN - 0767-3981
DOI - 10.1111/j.1472-8206.2004.00286_5.x
Subject(s) - aorta , medicine , endocrinology , thoracic aorta , apolipoprotein b , cholesterol , endothelium , acetylcholine , vasomotor , endothelial dysfunction , apolipoprotein e , chemistry , aortic root , nitric oxide , anatomy , disease
Previously we reported that even in old (18 months) apolipoprotein E‐deficient mice (apoE ‐/‐ ) on regular chow (RC), all nitric oxide (NO)‐mediated responses are preserved in plaque‐free vessels. Only when plaques develop, localised vasomotor dysfunction occurs. The impact of increased oxidative stress on relaxations was evaluated by feeding apoE ‐/‐ mice either a Western type diet (WD; 0.15% cholesterol, 41% fat) or RC (no cholesterol, 4% fat) for 8, 16 and 24 weeks. The aorta was systematically sectioned and segments of the aortic root (1 mm) and the thoracic aorta (5 × 2 mm, covering whole vessel, varying degrees of atherosclerosis) were studied in organ baths followed by morphometry. The WD enhanced plasma levels of total cholesterol (1382 ± 109 vs. 425 ± 21 mg/dl) and soluble ICAM‐1 (μg/ml; 8 weeks 43 ± 3 vs. 28 ± 1; 16 weeks 37 ± 2 vs. 25 ± 1; 24 weeks 41 ± 4 vs. 29 ± 1). In RC mice, relaxations to exogenous NO and acetylcholine (ACh) were preserved in all segments up to 24 weeks. When fed the WD however, maximum relaxation (E max ) to exogenous NO (acidified NaNO 2 ) was impaired in the aortic root at 8 (83 ± 3 vs. 92 ± 1%), 16 (71 ± 4 vs. 87 ± 3%) and 24 weeks (59 ± 7 vs. 83 ± 1%); shifts in the pD 2 values pointed to decreased sensitivity. ACh‐relaxation was unaltered at 8 weeks, but deteriorated in the aortic root at 16 (74 ± 6 vs. 99 ± 1%) and 24 weeks (51 ± 6% vs. 95 ± 3%). Similar changes occurred in the most distal thoracic aorta segment of WD mice. However, in all those segments plaques were detectable, and average lesion size was increased 6‐fold by the WD. Furthermore, responses to ACh (E max r s = −0.54; pD 2 r s = −0.36, P < 0.001) and exogenous NO (E max r s = −0.59; pD 2 r s = −0.30, P < 0.01) inversely correlated to plaque size in WD mice, as previously reported for RC apoE ‐/‐ mice. The dysfunction was apparent only after plaque development. Indeed, segments of the central thoracic aorta were largely free of atherosclerosis and showed unaltered relaxation, even after the onset of atherogenesis at 24 weeks WD. In conclusion, the elevation of soluble ICAM‐1 points to enhanced oxidative stress in WD apoE ‐/‐ mice. Yet, endothelium‐dependent relaxation is still maintained until plaques develop. As opposed to the human situation, endothelial dysfunction in hypercholesterolemic apoE ‐/‐ mice is not a systemic but a local process, strictly associated with lesion formation. Finally, the preservation of vasomotor responses in plaque‐free segments, and the correlation between lesion size and dysfunction, further emphasise that it is crucial to document plaque dimensions in vasomotor studies in atherosclerosis research.