Differential cholesteryl ester accumulation in two human vascular smooth muscle cell subpopulations exposed to aggregated LDL: effect of PDGF-stimulation and HMG-CoA reductase inhibition

Vascular smooth muscle cells (VSMC) are a major component of atheromatous p laque and they exhibit a high heterogeneity in morphology and proliferative activity. Two cell subpopulations from the media of human pulmonary artery were isolated according to the kinetics of outgrowth from the explants; th e first wave of cell outgrowth (VSMC-I) and the second wave (VSMC-II) were separately cultured. They were characterized by premitotic DNA synthesis ([ H-3]thymidine incorporation) and cholesterol synthesis ([C-14]acetate incor poration). DNA and cholesterol synthesis were approximately 13- and 5-fold, respectively, higher in VSMC-I than in VSMC-II. When these subpopulations were exposed to 100 mu g/ml of aggregated low density lipoproteins (agLDL), their cholesteryl ester (CE) content increased 4.3-fold over that induced by native LDL. The increase in CE induced by native or agLDL was approximat ely 2.7-fold higher in VSMC-I than in VSMC-II. These results suggest that a gLDL uptake is related, at least in part, to the cellular proliferative sta tus. Platelet derived growth factor (PDGF) did not increase agLDL uptake in any subpopulation, although it efficiently promoted proliferative activity in both cell types and increased native LDL uptake and cholesterol synthes is in VSMC-II. Simvastatin strongly inhibited CE accumulation from agLDL in VSMC-I, either unstimulated or PDGF-stimulated (> 80% inhibition). In cont rast, it only blocked agLDL uptake in PDGF stimulated VSMC-II (50% inhibiti on). Our results indicate that the quantitative effect of simvastatin on CE accumulation from agLDL is dependent on phenotypic cell characteristics an d it can be modulated in response to mitogenic stimulus. (C) 1999 Published by Elsevier Science Ireland Ltd. All rights reserved.