HDL-associated estradiol stimulates endothelial NO synthase and vasodilation in an SR-BI–dependent manner
Ming Gong, … , Annette Uittenbogaard, Eric J. Smart
Ming Gong, … , Annette Uittenbogaard, Eric J. Smart
Published May 15, 2003
Citation Information: J Clin Invest. 2003;111(10):1579-1587. https://doi.org/10.1172/JCI16777.
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Article Cardiology

HDL-associated estradiol stimulates endothelial NO synthase and vasodilation in an SR-BI–dependent manner

Abstract

Cardiovascular diseases remain the leading cause of death in the United States. Two factors associated with a decreased risk of developing cardiovascular disease are elevated HDL levels and sex — specifically, a decreased risk is found in premenopausal women. HDL and estrogen stimulate eNOS and the production of nitric oxide, which has numerous protective effects in the vascular system including vasodilation, antiadhesion, and anti-inflammatory effects. We tested the hypothesis that HDL binds to its receptor, scavenger receptor class B type I (SR-BI), and delivers estrogen to eNOS, thereby stimulating the enzyme. HDL isolated from women stimulated eNOS, whereas HDL isolated from men had minimal activity. Studies with ovariectomized and ovariectomized/estrogen replacement mouse models demonstrated that HDL-associated estradiol stimulation of eNOS is SR-BI dependent. Furthermore, female HDL, but not male HDL, promoted the relaxation of muscle strips isolated from C57BL/6 mice but not SR-BI null mice. Finally, HDL isolated from premenopausal women or postmenopausal women receiving estradiol replacement therapy stimulated eNOS, whereas HDL isolated from postmenopausal women did not stimulate eNOS. We conclude that HDL-associated estrodial is capable of the stimulating eNOS. These studies establish a new paradigm for examining the cardiovascular effects of HDL and estrogen.

Authors

Ming Gong, Melinda Wilson, Thomas Kelly, Wen Su, James Dressman, Jeanie Kincer, Sergey V. Matveev, Ling Guo, Theresa Guerin, Xiang-An Li, Weifei Zhu, Annette Uittenbogaard, Eric J. Smart

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HDL-induced relaxation is SR-BI and endothelium dependent. (a) Endotheli...
HDL-induced relaxation is SR-BI and endothelium dependent. (a) Endothelium-intact femoral artery strips isolated from C57BL/6 or SR-BI null mice were precontracted with 30 nM 5-hydroxytryptamine. Acetylcholine (1 μM) or 10 μg/ml HDL purified from female mice was then added to the tissue bath, and the extent of relaxation was measured. Six muscle strips were used for each group. Black bars represent C57BL/6 mice and white bars SR-BI null mice. (b) Endothelium-intact or endothelium-denuded femoral artery strips isolated from control C57BL/6 mice were precontracted with 30 nM 5-hydroxytryptamine. Acetylcholine (1 μM) or 10 μg/ml HDL purified from female mice was then added to the tissue bath, and the extent of relaxation was measured. Three to six muscle strips were used for each group. Black bars represent endothelium intact and white bars endothelium denuded.