Cell-surface estrogen receptors mediate calcium-dependent nitric oxide release in human endothelia

Circulation. 2000 Apr 4;101(13):1594-7. doi: 10.1161/01.cir.101.13.1594.


Background: Although estrogen replacement therapy has been associated with reduction of cardiovascular events in postmenopausal women, the mechanism for this benefit remains unclear. Because nitric oxide (NO) is considered an important endothelium-derived relaxing factor and may function to protect blood vessels against atherosclerotic development, we investigated the acute effects of physiological levels of estrogen on NO release from human internal thoracic artery endothelia and human arterial endothelia in culture.

Methods and results: We tested the hypothesis that estrogen acutely stimulates constitutive NO synthase activity in human endothelial cells by acting on a cell-surface receptor. NO release was measured in real time with an amperometric probe. 17beta-Estradiol exposure to internal thoracic artery endothelia and human arterial endothelia in culture stimulated NO release within seconds in a concentration-dependent manner. 17beta-Estradiol conjugated to bovine serum albumin also stimulated NO release, suggesting action through a cell-surface receptor. Tamoxifen, an estrogen receptor inhibitor, antagonized this action. We further showed with the use of dual emission microfluorometry that 17beta-estradiol-stimulated release of endothelial NO was dependent on the initial stimulation of intracellular calcium transients.

Conclusions: Physiological doses of estrogen immediately stimulate NO release from human endothelial cells through activation of a cell-surface estrogen receptor that is coupled to increases in intracellular calcium.

Publication types

  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Adult
  • Aged
  • Arteries / metabolism
  • Calcium / physiology*
  • Cell Membrane / metabolism*
  • Endothelium, Vascular / metabolism*
  • Estradiol / metabolism
  • Estradiol / pharmacology
  • Estrogen Antagonists / pharmacology
  • Female
  • Humans
  • In Vitro Techniques
  • Intracellular Membranes / metabolism
  • Male
  • Nitric Oxide / metabolism*
  • Receptors, Estrogen / physiology*
  • Tamoxifen / pharmacology


  • Estrogen Antagonists
  • Receptors, Estrogen
  • Tamoxifen
  • Nitric Oxide
  • Estradiol
  • Calcium