Administration of estrogen to cholesterol-fed rabbits dramatically retarded arterial lesion development despite its lack of effect on plasma cholesterol concentration and on llpoprotein patterns. Cholesteryl ester influx into the aortic wall was also much lower in the estrogen-treated animals and paralleled the aortic cholesterol content in treated and untreated animals; the fraction of aortic cholesteryl ester lost by efflux was the same in treated and untreated animals. The fraction of newly entered cholesteryl ester hydrolyzed by aorta was significantly reduced In the estrogen-treated animals. Low cholesteryl ester Influx and relatively less hydrolysis of cholesteryl ester by the aorta may be indicative of reduced Internallzatlon of plasma cholesteryl ester by aortic cells, which may in turn account for the reduced atherogenesis in the estrogen-treated rabbits. (Arteriosclerosis 6:57-63, January/February 1986) I t has been well documented that premenopausal women have a lower incidence of heart disease than men. Ovariectomy and menopause cause the loss of this "resistance" to coronary events, 12 and estrogens have been thought to provide this "protective" effect.3 Kushwaha and Hazzard 4 have shown that estrogen retards the development of atherosclerosis in cholesterol-fed rabbits. They attribute this to a lowering of the plasma cholesterol levels, in particular the very low density lipoprotein fraction. However, others have found that estrogen may have a protective effect without any alterations in plasma cholesterol levels.56 Estrogen administration has also been shown to alter aortic enzyme activities, 78 to inhibit increased arterial collagen and elastin, a 10 to enhance prostacyclin synthesis, 11 and to alter platelet aggregation.1213 Therefore, estrogen may act directly on the arterial wall, possibly mediated by estrogen receptors thought to be present in arterial tissue. tration of estrogen to atherosclerosis-susceptible White Carneau pigeons increased the activity of arterial lysosomal cholesteryl ester hydrolase and decreased the activity of cholesteryl ester synthetase when these enzymes were measured in vitro. Others have reported 6 that after the administration of estrogens to pigeons with pre-existing arterial lesions, their arteries contained relatively less lipid material than did the arteries from the untreated group. These studies suggest that, in addition to alterations in plasma cholesterol levels, estrogen may retard atherogenesis by altering the lipid metabolism of the arterial wall.The present study reports that estrogen retards atherogenesis with no effect on the plasma cholesterol levels in the cholesterol-fed rabbit. The effects of estrogen administration on the influx and metabolism of cholesteryl ester in the aortas of cholesterolfed rabbits in vivo are also reported.

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Total plasma lipoproteins were labeled with radioactive cholesteryl ester or cholesteryl ether by transfer of these lipids from phosphatidylcholine vesicles in the presence of plasma lipid transfer activity. Intravenous injection of these preparations into hypercholesterolemic rabbits showed disappearance curves identical to those of in vivo labeled lipoproteins. Disappearance of cholesteryl ester and ether were similar during the first 24 hours, but they diverged at later time intervals, indicating recirculation of labeled cholesteryl ester. Lipoproteins labeled with cholesteryl ether were injected at 25 days, 7 days and 1 day before sacrifice of the rabbits. The maximal loss of labeled ether from the aortas during a 24-hour period ranged from 1.6% to 8.9% of the labeled ether taken up from plasma. Hydrolysis of cholesteryl ester by the artery during 24 hours averaged 35% of the calculated cholesteryl ester influx. After hydrolysis, cholesteryl ester fatty acid appeared to be esterified more rapidly than the cholesterol moiety of the cholesteryl ester.