Gender gap in aortic cholesterol accumulation in cholesterol-clamped rabbits: role of the endothelium and mononuclear-endothelial cell interaction.

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.