Estradiol induces the calcium-dependent translocation of endothelial nitric oxide synthase

  • Goetz R
  • Thatte H
  • Prabhakar P
 et al. 
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Although estrogen is known to stimulate nitric oxide synthesis in vascular endothelium, the molecular mechanisms responsible for this effect remain to be eluci-dated. Using quantitative immunof luorescence imaging ap-proaches, we have investigated the effect of estradiol on the subcellular targeting of endothelial nitric oxide synthase (eNOS) in bovine aortic endothelial cells. In unstimulated endothelial cells, eNOS is predominantly localized at the cell membrane. Within 5 min after the addition of estradiol, most of the eNOS translocates from the membrane to intracellular sites close to the nucleus. On more prolonged exposure to estradiol, most of the eNOS returns to the membrane. This effect of estradiol is evident at a concentration of 1 pM, and a maximal estradiol effect is seen at a concentration of 1 nM. Neither progesterone nor testosterone has any effect on eNOS distribution. After estradiol addition, a transient rise in intracellular Ca 2؉ concentration precedes eNOS transloca-tion. Both the Ca 2؉ -mobilizing and eNOS-translocating ef-fects of estradiol are completely blocked by the estrogen receptor antagonist ICI 182,780, and the intracellular Ca 2؉ chelator 1,2-bis-(o-aminophenoxy)ethane-N,N,N؅,N؅-tetraace-tic acid (BAPTA) prevents estradiol-induced eNOS translo-cation. Use of the nitric oxide-specific dye diaminof luorescein shows that estradiol treatment increases nitric oxide gener-ation by endothelial cells; this response is blocked by ICI 182,780 and by the eNOS inhibitor N ␻ -nitro-L-arginine. These results show that estradiol induces subcellular translocation of eNOS by a rapid, Ca 2؉ -dependent, receptor-mediated mechanism, and they suggest a nongenomic role for estrogen in the modulation of NO-dependent vascular tone. Estrogen was identified as a vasodilator nearly 60 years ago. In 1940, Reynolds and Foster reported marked dilation of the ear microvasculature within minutes after injection of estrogen into ovariectomized rabbits (1). The molecular mechanism underlying the estrogen-induced vasodilation is not defined. Several studies suggest that a key mediator of this vasodilator response could be the endothelium-derived relaxing factor, nitric oxide (NO), and that estrogen stimulates NO synthesis in vascular endothelium. Kawano et al. (2) found changes in endothelium͞NO-dependent vasomotion in parallel with the cyclical hormonal changes in premenopausal women, with the greatest potentiation at peak plasma levels of estrogen. Several groups (3–5) reported that estrogen potentiates or restores endothelium-dependent coronary vasodilation in postmeno-pausal women; Guetta et al. (6) showed that these effects are mediated by NO. Van Buren et al. (7) and Rosenfeld et al. (8) identified NO as the principal mediator of estrogen-induced dilation of ovine uterine vasculature. More recently, Lantin-Hermoso et al. (9) and Caulin-Glaser et al. (10) found that

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  • Regina M Goetz

  • Hemant S Thatte

  • Prakash Prabhakar

  • Michael R Cho

  • Thomas Michel

  • David E Golan

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