Oxidized low density lipoproteins potentiate vasoconstrictions to various agonists by direct interaction with vascular smooth muscle

Abstract

In hypercholesterolemia, low density lipoproteins (LDLs) may be oxidized by monocytes/macrophages in the arterial wall. Therefore, we investigated the effect of LDL and its oxidative derivatives (ox-LDL) on vascular tone in isolated perfused rabbit femoral arteries. Perfusion of endothelium-intact and endothelium-denuded segments with ox-LDL (80 micrograms protein/ml) caused no or only weak vasoconstrictions in the absence of contractile agonists. However, in the presence of ox-LDL, vasoconstrictions to threshold concentrations of norepinephrine, serotonin, phenylephrine, or potassium were significantly enhanced. This enhancement correlated with the degree of oxidation. When ox-LDL was administered at higher concentrations (greater than 200 micrograms protein/ml), it evoked moderate vasoconstrictions even in the absence of contractile agonists. Native LDL had no effect on vascular tone. Preincubation with verapamil, diltiazem, and nitrendipine inhibited vasoconstrictions evoked by ox-LDL, both in the presence and in the absence of a contractile agonist. The contractile responses to ox-LDL were significantly greater in endothelium-denuded segments than in endothelium-intact segments. At the above concentrations, ox-LDL had no influence on endothelium-derived relaxing factor-mediated vasodilations. These data indicate that ox-LDL enhances agonist-induced vasoconstrictions by a direct effect on the vascular smooth muscle. We therefore suggest that ox-LDL is an important factor that may increase the risk of inappropriate vasoconstriction in hypercholesterolemia, independent of its putative cytotoxic effect on the endothelium.