NITRIC-OXIDE MEDIATES LDL UPTAKE IN THE ARTERY WALL IN RESPONSE TO HIGH-CONCENTRATIONS OF 17-BETA-ESTRADIOL

Female sex hormones are known to affect lipoprotein flux in the artery wall and atherosclerosis. However, the mechanisms of these artery wal l effects are unclear. To examine the effect of 17 beta-estradiol (est radiol) on LDL uptake in the artery wall, we developed an isolated per fused rat carotid artery model from ovariectomized rats. LDL flux in t he artery wall was measured by quantitative fluorescence microscopy be fore and after treatment with estradiol (0.001 to 10 000 nmol/L). Dose -response experiments showed no significant difference in the rate of LDL uptake when arteries were perfused with estradiol at physiological concentrations (0.001 to 1 nmol/L) compared with control perfusions. However, higher concentrations of estradiol (10 to 10 000 nmol/L) sign ificantly increased the rate of LDL uptake in isolated arteries. Arter y lumen volume significantly increased with perfusion of estradiol (1 to 100 nmol/L) but decreased after perfusions of higher concentrations of estradiol (1000 to 10 000 nmol/L). Additional studies were perform ed to examine mechanisms of estradiol-mediated increases in LDL uptake . The effect of estradiol (10 nmol/L) on the rate of LDL uptake was bl ocked by nitric oxide synthase inhibitors. However, the estrogen recep tor antagonist tamoxifen did not block the effects of estradiol on the rate of LDL uptake. Our study indicates that modulation of LDL uptake in the artery wall by estradiol is concentration dependent. High conc entrations of estradiol increase LDL uptake by production of endotheli um-derived nitric oxide. These observations suggest that increased nit ric oxide production compromises endothelial layer barrier function to increase LDL uptake in the artery wall.