ATHEROSCLEROSIS, VASCULAR REMODELING, AND IMPAIRMENT OF ENDOTHELIUM-DEPENDENT RELAXATION IN GENETICALLY ALTERED HYPERLIPIDEMIC MICE

We examined the vascular structure and endothelium-dependent relaxatio n in two genetic models of hypercholesterolemia: apolipoprotein E (apo E)-knockout mice and combined apoE/LDL receptor-double-knockout mice. Intimal area was increased markedly in proximal segments of thoracic a ortas from apoE/LDL receptor-knockout mice [0.13+/-0.03 (mean+/-SE) mm (2)] compared with normal (C57BL/6J) mice (0.002+/-0.002 mm(2), P<.05) . Despite intimal thickening, the vascular lumen was not smaller in th e aortas of apoE/LDL receptor-knockout mice (0.52+/-0.03 mm(2)) than i n normal mice (0.50+/-0.03 mm(2)). In apoE-deficient mice, intimal thi ckening was minimal or absent, even though the concentration of plasma cholesterol was only modestly less than that in the double-knockout m ouse (14.9+/-1.1 vs 18.0+/-1.2 mmol/L, respectively, P<.05). Relaxatio n of the aorta was examined in vitro in vascular rings precontracted w ith U46619. In normal mice, acetylcholine produced relaxation, which w as markedly attenuated by the nitric oxide synthase inhibitor N-G-nitr o-L-arginine (100 mu M) Relaxation to acetylcholine and the calcium io nophore A23187 was normal in apoE-deficient mice (in which lesions wer e minimal) but greatly impaired in the proximal segments of thoracic a ortas of apoE/LDL receptor-deficient mice, which contained atheroscler otic lesions. Vasorelaxation to nitroprusside was similar in normal an d apoE-knockout mice, with modest but statistically significant impair ment in atherosclerotic segments of apoE/LDL receptor-knockout mice. I n distal segments of the thoracic aorta of apoE/LDL receptor-deficient mice, atherosclerotic lesions were minimal or absent, and the endothe lium-dependent relaxation to acetylcholine and calcium ionophore was n ormal. Thus, in apoE/LDL receptor-knockout mice (a genetic model of hy perlipidemia), there is vascular remodeling with preservation of the a ortic lumen despite marked intimal thickening, with impairment of endo thelium-dependent relaxation to receptor-and nonreceptor-mediated agon ists. Atherosclerosis may be accelerated in the apoE/LDL receptor-doub le-knockout mouse compared with the apoE-knockout strain alone. We spe culate that other factors, such as the absence of LDL receptors, may c ontribute to the differences in the extent of atherosclerosis in these two models of hyperlipidemia.