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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Figure 1

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HDL isolated from female subjects stimulates the production of nitric ox...
HDL isolated from female subjects stimulates the production of nitric oxide. HDL, LDL, and VLDL were isolated from young, reproductively competent female humans (a) and mice (b) and age-matched male humans (a) and mice (b) (31). The freshly isolated lipoproteins (10 μg/ml) were incubated with human microvascular endothelial cells that had been prelabeled with 0.75 μCi/ml of [3H]arginine for 15 minutes at 37°C (21). An additional set of cells was treated with 1 μg/ml of ionomycin to determine the maximal eNOS stimulation. The cells were then washed, lysed, and extracted, and radiolabeled arginine was separated from radiolabeled citrulline using an ion-exchange column. Each experiment included controls, using 1 mM L-NNA to demonstrate that over 99% of the generated citrulline was due to eNOS activity (data not shown). In (c), a concentration curve of the effect of female HDL on eNOS activity is shown. The data are from six to eight independent experiments, with triplicate measurements in each experiment (mean ± SE).