17 beta-Estradiol acts separately on the LDL particle and artery wall to reduce LDL accumulation

Estrogen replacement therapy has been should to attenuate atherogenesis, al though the mechanisms for this effect are incompletely defined. Previously, we shelved that 17-beta estradiol (estradiol) attenuated oxidant stress-in duced increases in vascular low density lipoprotein (LDL) accumulation. It was unclear whether estradiol's effect was imparted on the lipoprotein part icle or the artery wall. To examine this, we chronically treated rats with the following sex hormones: low estradiol, high estradiol, progesterone, lo w estradiol + progesterone, placebo, or control. Carotid arteries (n = 8/gr oup) were isolated and pel fused with fluorescently labeled LDL, Rates of L DL accumulation were measured before and after treatment with 10 ng/ml tumo r necrosis factor-alpha (TNF) using quantitative fluorescence microscopy, W e observed a 50% decrease in basal LDL accumulation rates (P < 0.01) and a 25% decrease in endothelial layer permeability (P < 0.01) in artel ies from estradiol-treated animals. There was no effect of hormone replacement on r ate of TNF-induced LDL accumulation (P = 0.451), while incubation of LDL wi th 65 pg/ml estradiol attenuated the TNF effect (P < 0.01).jlr These experi ments suggest two independent mechanisms of anti-atherogenic protection by estradiol: 1) decreased endothelial layer permeability; and 2) incorporatio n of estradiol into the LDL particle and prevention of LDL binding to the a rtery wall.