Gender Gap in Aortic Cholesterol Accumulation in Cholesterol-Clamped Rabbits

BACKGROUND: The purpose of the present study was to investigate plasma lipid-independent mechanisms for the sex difference in the development of atherosclerosis. METHODS AND RESULTS: In the first experiment, 20 male and 20 female rabbits were balloon-injured in the middle thoracic aorta and maintained at the same plasma cholesterol level of approximately 25 mmol/L by use of individualized cholesterol feeding for 13 weeks. In the undamaged aorta, female rabbits had accumulated less than half the amount of cholesterol found in male rabbits (P<0.05). In the balloon-injured aorta, cholesterol accumulation was 3- to 4-fold higher than in the undamaged aorta, with no difference between groups. When cholesterol accumulation data for the balloon-injured aorta were separately assessed for blue (deendothelialized) and white (reendothelialized) tissue, blue tissue surprisingly revealed a reverse gender gap, ie, a significantly higher accumulation of cholesterol in females than in males (P<0.05). White tissue, which constituted the majority of the balloon-injured area, showed no difference in aortic cholesterol accumulation between groups. In the second experiment, 6 male and 6 female rabbits were fed standard rabbit pellets and 6 male and 6 female rabbits were fed a 0.5% cholesterol-enriched chow for 2 weeks. Mononuclear cell binding was 5-fold higher in aortic segments from hypercholesterolemic than from normocholesterolemic rabbits (P<0. 001). In hypercholesterolemic rabbits, cell binding was significantly lower in female than in male rabbits (P<0.05) and showed higher values in atherosclerosis-prone regions. These differences were not found in normocholesterolemic animals. CONCLUSIONS: The present results suggest that female atheroprotection is independent of sex differences in plasma cholesterol but vitally dependent on the state of the arterial endothelium and involves mononuclear-endothelial cell adhesion as an early step.