Dehydroepiandrosterone increases endothelial cell proliferation in vitro and improves endothelial function in vivo by mechanisms independent of androgen and estrogen receptors

J Clin Endocrinol Metab. 2004 Sep;89(9):4708-15. doi: 10.1210/jc.2003-031560.

Abstract

Dehydroepiandrosterone (DHEA) may be beneficial in cardiovascular health, but mechanisms of DHEA action in the cardiovascular system are unclear. We have therefore 1) determined DHEA effects on the proliferation of cultured endothelial cells (EC), 2) compared effects of DHEA with estradiol (E) and testosterone (T), and 3) examined DHEA effects on subcellular messengers. We have in addition examined effects of DHEA (100 mg/d, 3 months) in 36 healthy postmenopausal women on blood pressure, lipids, and endothelial function, assessed noninvasively in large vessels by flow-mediated dilation of the brachial artery during reactive hyperemia, and in small vessels by laser Doppler velocimetry with iontophoresis of acetylcholine. DHEA, E, and T all increased EC proliferation; the effect of E was abolished by the estrogen receptor antagonist ICI 182,780, and that of T was abolished by the androgen receptor antagonist flutamide; neither blocked the effect of DHEA. In vitro, DHEA increased EC expression of endothelial nitric oxide synthase and activity of extracellular signal-regulated kinase 1/2. In vivo, DHEA increased flow-mediated dilation and laser Doppler velocimetry and reduced total plasma cholesterol. Thus, DHEA increases EC proliferation in vitro by mechanism(s) independently of either androgen receptor or estrogen receptor and in vivo enhances large and small vessel EC function in postmenopausal women.

Publication types

  • Clinical Trial
  • Randomized Controlled Trial
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Aged
  • Animals
  • Brachial Artery / drug effects
  • Brachial Artery / physiology
  • Cattle
  • Cell Division / drug effects
  • Cells, Cultured
  • Dehydroepiandrosterone / pharmacology*
  • Double-Blind Method
  • Endothelial Cells / drug effects*
  • Endothelial Cells / physiology
  • Estradiol / analogs & derivatives*
  • Estradiol / pharmacology
  • Female
  • Flutamide / pharmacology
  • Fulvestrant
  • Humans
  • Middle Aged
  • Mitogen-Activated Protein Kinases / metabolism
  • Nitric Oxide Synthase / metabolism
  • Nitric Oxide Synthase Type III
  • Receptors, Androgen / physiology*
  • Receptors, Estrogen / physiology*
  • Skin / blood supply
  • Testosterone / pharmacology

Substances

  • Receptors, Androgen
  • Receptors, Estrogen
  • Fulvestrant
  • Testosterone
  • Dehydroepiandrosterone
  • Estradiol
  • Flutamide
  • NOS3 protein, human
  • Nitric Oxide Synthase
  • Nitric Oxide Synthase Type III
  • Mitogen-Activated Protein Kinases