Exposure to oxidized low-density lipoprotein in vivo enhances intimal thickening and selectively impairs endothelium-dependent dilation in the rabbit.
OBJECTIVE
Based on in vitro studies, oxidized low-density lipoprotein (oxLDL) has been implicated in atherogenesis and the associated deficiency in endothelium-dependent relaxation. The aim of this study was to investigate the effects of in vivo exposure to oxLDL on intimal thickening and relaxing behaviour.


METHODS
Intimal thickening was evoked by the placement of silicone collars around the carotid arteries of the rabbit for 3 or 14 days. OxLDL (Cu(2+)-oxidized, 7 micron/h) or the vehicle phosphate-buffered saline (PBS) was infused in the collars via subdermally implanted osmotic minipumps.


RESULTS
The collared vessels receiving PBS developed discrete intimal thickening after 14 days (intima/media (I/M) ratio 11 +/- 2%). OxLDL infusion resulted in intimal thickening after 3 days and significantly enhanced the intimal thickness 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 donors glyceryl trinitrate (GTN) and S-nitroso-N-acetylpenicillamine (SNAP). However, the sensitivity to acetylcholine was decreased after exposure to oxLDL for 14 days (-logEC50 oxLDL 6.95 +/- 0.11 vs. 7.52 +/- 0.11 collar alone) and the maximal relaxation to the endothelium-dependent agonist was reduced by 50%, this in the presence of a virtually intact endothelium. Complete relaxation was still obtained with the nitric oxide donors.


CONCLUSIONS
Our results show for the first time that local vascular exposure to oxLDL in vivo promotes intimal thickening and inhibits endothelium-dependent dilation, thereby supporting an active role for oxLDL in the morphological and functional changes observed in atherosclerotic blood vessels.
Matthys
K E
KE
Division of Pharmacology (UIA), University of Antwerp, Wilrijk, Belgium. matthysk@uia.ua.ac.be
Van Hove
C E
CE
Kockx
M M
MM
Andries
L J
LJ
Van Osselaer
N
N
Herman
A G
AG
Bult
H
H
D000109:Acetylcholine / Q000494:pharmacology; D000818:Animals; D000001:Calcimycin / Q000494:pharmacology; D003300:Copper / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004730:Endothelium, Vascular / Q000187:drug effects*; D007476:Ionophores / Q000494:pharmacology; D015227:Lipid Peroxidation; D008077:Lipoproteins, LDL / Q000378:metabolism / Q000494:pharmacology*; D008297:Male; D005996:Nitroglycerin / Q000494:pharmacology; D010396:Penicillamine / Q000031:analogs & derivatives / Q000494:pharmacology; D010656:Phenylephrine / Q000494:pharmacology; D011817:Rabbits; D026423:S-Nitroso-N-Acetylpenicillamine; D017539:Tunica Intima / Q000187:drug effects* / Q000473:pathology; D014662:Vasoconstrictor Agents / Q000494:pharmacology; D014664:Vasodilation / Q000187:drug effects*; D014665:Vasodilator Agents / Q000494:pharmacology
D007476:Ionophores; D008077:Lipoproteins, LDL; D014662:Vasoconstrictor Agents; D014665:Vasodilator Agents; D010656:Phenylephrine; D000001:Calcimycin; D003300:Copper; D026423:S-Nitroso-N-Acetylpenicillamine; C028419:cuprous chloride; D005996:Nitroglycerin; D010396:Penicillamine; D000109:Acetylcholine