EXPOSURE TO OXIDIZED LOW-DENSITY-LIPOPROTEIN IN-VIVO ENHANCES INTIMALTHICKENING AND SELECTIVELY IMPAIRS ENDOTHELIUM-DEPENDENT DILATION IN THE RABBIT

Objectives: Based on in vitro studies, oxidized low-density lipoprotei n (oxLDL) has been implicated in atherogenesis and the associated defi ciency in endothelium-dependent relaxation. The aim of this study was to investigate the effects of in vivo exposure to oxLDL on intimal thi ckening and relaxing behaviour. Methods: Intimal thickening was evoked by the placement of silicone collars around the carotid arteries of t he rabbit for 3 or 14 days. OxLDL (Cu2+-oxidized, 7 mu g/h) or the veh icle phosphate-buffered saline (PBS) was infused in the collars via su bdermally implanted osmotic minipumps. Results: The collared vessels r eceiving PBS developed discrete intimal thickening after 14 days (inti ma/media (I/M) ratio ii +/- 2%). OxLDL infusion: resulted in intimal t hickening after 3 days and significantly enhanced the intimal thicknes s by 14 days (I/M ratio 98 +/- 16%). Collaring alone for 3 or 14 days and 3 days exposure to oxLDL did not impair the endothelium-dependent relaxations to acetylcholine or calcium ionophore, nor to the NO donor s glyceryl trinitrate (GTN) and S-nitroso-N-acetylpenicillamine (SNAP) . However, the sensitivity to acetylcholine was decreased after exposu re to oxLDL for 14 days (-logEC(50) oxLDL 6.95 +/- 0.11 vs. 7.52 +/- 0 .11 collar alone) and the maximal relaxation to the endothelium-depend ent agonist was reduced by 50%, this in the presence of a virtually in tact endothelium. Complete relaxation was still obtained with the nitr ic oxide donors. Conclusion: Our results show for the first time that local vascular exposure to oxLDL in vivo promotes intimal thickening a nd inhibits endothelium-dependent dilation, thereby supporting an acti ve role for oxLDL in the morphological and functional changes observed in atherosclerotic blood vessels. (C) 1998 Elsevier Science B.V.