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 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.
Roberts
K A
KA
Division of Cardiovascular Medicine, University of California, Davis 95616, USA.
Woo
M M
MM
Rutledge
J C
JC
D000818:Animals; D002339:Carotid Arteries / Q000187:drug effects* / Q000378:metabolism; D004958:Estradiol / Q000494:pharmacology*; D005260:Female; D006801:Humans; D008077:Lipoproteins, LDL / Q000378:metabolism*; D008297:Male; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology; D009569:Nitric Oxide / Q000502:physiology*; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors; D010477:Perfusion; D051381:Rats; D017207:Rats, Sprague-Dawley; D013629:Tamoxifen / Q000494:pharmacology; D013739:Testosterone / Q000494:pharmacology
D008077:Lipoproteins, LDL; D013629:Tamoxifen; D009569:Nitric Oxide; D013739:Testosterone; D004958:Estradiol; D019001:Nitric Oxide Synthase; D019331:NG-Nitroarginine Methyl Ester