Physiological Concentration of 17b-Estradiol Retards the Progression of Severe Atherosclerosis Induced by a High-Cholesterol Diet Plus Balloon Catheter Injury Role of NO

The molecular mechanisms of the antiatherosclerotic effects of estrogen are not yet known. We evaluated the effects of 17b-estradiol (E2) on high cholesterol diet– (HCD; standard diet and 1% cholesterol) and balloon injury–induced atherosclerosis in female New Zealand White rabbits. The abdominal aortas of 40 oophorectomized (Groups 1 through 5) and 8 nonoophorectomized (Group 6) rabbits were injured by balloon catheter, and the animals were then divided into the following groups and treated for 10 weeks: Group 1, standard diet; Group 2, standard diet plus a moderate dose of E2 (100 mg z kg 21 z d); Group 3, HCD; Group 4, HCD plus a moderate dose of E2; Group 5, HCD plus a low dose of E2 (20 mg z kg 21 z d); and Group 6, HCD in nonoophorectomized rabbits. After the treatment phase, plasma E2 was increased up to 282.2645.5 pg/mL in Group 2, 263.0641.5 pg/mL in Group 4, 87.9618.8 pg/mL in Group 5, and 45.667.3 pg/mL in Group 6. HCD-mediated increases in plasma lipid levels were not changed by E2 treatment, whereas E2 decreased the aortic intimal thickening in Group 2 animals compared with those in Group 1 and reduced atherosclerosis in the thoracic and abdominal aortas of Group 4, 5, and 6 rabbits compared with those in Group 3. E2 restored the impaired abdominal aortic endothelium–dependent relaxation of balloon-injured and HCDsupplemented rabbits, and E2 increased basal nitric oxide (NO) release. The basal NO–releasing effect showed a significant, inverse relation with the severity of atherosclerosis. Plasma E2 concentration also showed a significant, inverse relation with atherosclerotic area. In conclusion, physiological concentrations of E2 can retard the progression of severe atherosclerosis and stabilize atheromas induced by HCD and balloon injury. The retardation may be partially mediated by endothelial NO function in vessels treated with E2. (Arterioscler Thromb Vasc Biol. 2000;20:1613-1621.)