Nitric Oxide Mediates LDL Uptake in the Artery Wall in Response to High Concentrations of 17β-Estradiol

Abstract

Female sex hormones are known to affect lipoprotein flux in the artery wall and atherosclerosis. However, the mechanisms of these artery wall effects are unclear. To examine the effect of 17 beta-estradiol (estradiol) on LDL uptake in the artery wall, we developed an isolated perfused rat carotid artery model from ovariectomized rats. LDL flux in the artery wall was measured by quantitative fluorescence microscopy before 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) significantly increased the rate of LDL uptake in isolated arteries. Artery 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 performed to examine mechanisms of estradiol-mediated increases in LDL uptake. The effect of estradiol (10 nmol/L) on the rate of LDL uptake was blocked by nitric oxide synthase inhibitors. However, the estrogen receptor 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 concentrations of estradiol increase LDL uptake by production of endothelium-derived nitric oxide. These observations suggest that increased nitric oxide production compromises endothelial layer barrier function to increase LDL uptake in the artery wall.

Modified LDL–Mediated Increases in Endothelial Layer Permeability Are Attenuated With 17β-Estradiol

“…Physiological concentrations of estrogens have been shown to act directly on the artery wall, 32,34 to attenuate atherosclerosis, 35 and to reduce morbidity and mortality associated with atherosclerotic cardiovascular disease in postmenopausal women. 36 In comparison, supraphysiolgical concentrations of some estrogens (for example, 17␤-estradiol) can increase LDL accumulation in the artery wall.…”

“…36 In comparison, supraphysiolgical concentrations of some estrogens (for example, 17␤-estradiol) can increase LDL accumulation in the artery wall. 32 However, the mechanisms by which estrogens affect the interaction of MM-LDL with the artery wall are incompletely understood and were, therefore, the subject of this article.…”

“…32 The rates of DiI-N-LDL, DiI-MM-LDL, and DiI-OX-LDL efflux were determined, as we have described previously. 6 In summary, the rate of decay of fluorescence intensity was determined after the fluorescently labeled LDL solution was washed from the vessel lumen.…”

“…This concentration of estradiol has been shown not to affect the rate of LDL accumulation in the artery wall in short-term studies. 32 After estradiol was added to both the nonfluorescent and the fluorescently labeled LDL solutions, the artery was perfused for 10 minutes with the nonfluorescent solution. Then, the artery was perfused with the fluorescently labeled LDL solution for 10 minutes.…”

Experimental Abdominal Aortic Aneurysms in Mice Lacking Expression of Inducible Nitric Oxide Synthase

“…Although it remains unclear why these effects might occur in a sexselective fashion and how they are related to circulating ovarian hormones, there is increasing evidence that interactions between estrogen and cellular NOS expression can influence NO production in various pathophysiologic states. 53,[65][66][67][68] More comprehensive studies will be needed to elucidate the apparent interaction between ovarian hormones and NO production during aneurysm formation in female mice.…”