Inhibition of vascular smooth muscle cell migration by intact endothelium is nitric oxide-mediated: interference by oxidised low density lipoproteins.
Migration of vascular smooth muscle cells (SMCs) leading to neointimal hyperplasia is an early and cardinal feature of atherogenesis. Migration of rat aortic SMCs from an upper chamber towards a lower one has been studied in a microchemotaxis (Boyden) chamber. Spontaneous migration of SMCs was practically prevented by the presence of endothelium in the lower chamber and was reduced if endothelial cells were substituted with endothelial cell-conditioned medium. Endothelial cells which had been treated with either the inhibitor of protein synthesis cycloheximide or nitric oxide synthesis N(G)-nitro-L-arginine showed no inhibitory effect on SMC migration. Addition of a nitric oxide donor S-nitroso-N-acetylpenicillamine to cell-free medium in the lower chamber prevented SMC migration. Addition of native LDL to endothelial cells had no effect on SMC migration, while (UV light) oxidised LDL completely abolished the inhibitory effect of endothelial cells on SMC migration. It is concluded that via nitric oxide, endothelium exerts a powerful inhibitory effect on SMC migration. This effect of intact endothelium is completely abolished by oxidised LDL applied in a concentration, which is relevant to those measured in plasma of patients with severe coronary artery disease. It is suggested that oxidised LDL may contribute to the pathogenesis of atherogenesis by stimulating migration of SMCs from media to the intima via abolishing the physiological inhibitory effect of normal endothelium.
Gorog
P
P
Pathopharmacology Unit, The William Harvey Research Institute, London, UK.
Kovacs
I B
IB
D000818:Animals; D002465:Cell Movement / Q000187:drug effects / Q000502:physiology; D017077:Culture Media, Conditioned / Q000494:pharmacology; D003513:Cycloheximide / Q000494:pharmacology; D004730:Endothelium, Vascular / Q000166:cytology / Q000187:drug effects / Q000502:physiology*; D004791:Enzyme Inhibitors; D008077:Lipoproteins, LDL / Q000494:pharmacology; D008297:Male; D009131:Muscle, Smooth, Vascular / Q000166:cytology* / Q000187:drug effects / Q000502:physiology*; D009569:Nitric Oxide / Q000037:antagonists & inhibitors / Q000502:physiology*; D019335:Nitroarginine; D010396:Penicillamine / Q000031:analogs & derivatives / Q000494:pharmacology; D011500:Protein Synthesis Inhibitors / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D026423:S-Nitroso-N-Acetylpenicillamine; D013997:Time Factors
D017077:Culture Media, Conditioned; D004791:Enzyme Inhibitors; D008077:Lipoproteins, LDL; D011500:Protein Synthesis Inhibitors; C099252:oxidized low density lipoprotein; D019335:Nitroarginine; D009569:Nitric Oxide; D026423:S-Nitroso-N-Acetylpenicillamine; D003513:Cycloheximide; D010396:Penicillamine