Estrogen acutely stimulates endothelial nitric oxide synthase in H441 human airway epithelial cells

Erica A. Kirsch, Ivan S. Yuhanna, Zhong Chen, Zohre German, Todd S. Sherman, Philip W. Shaul

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64 Scopus citations


Nitric oxide (NO) is an important mediator of physiologic processes in the airway. Levels of exhaled NO are greatest and asthma symptoms are least in menstruating women during midcycle, when estrogen levels are highest. To better understand the role of estrogen in airway function, we tested the hypothesis that estrogen stimulates endothelial NO synthase (eNOS) in NCI-H441 human bronchiolar epithelial cells. eNOS activation was assessed by measuring conversion of [3H]L-arginine to [3H]L-citrulline in intact cells. eNOS activity rose in the presence of estradiol-17β (E2β), with a maximum stimulation of 243% at 10-8 M E2β. This response was comparable to the 201% increase elicited by the calcium (Ca2+) ionophore A23187 (10-5 M), and was evident as early as 5 min after such treatment. Actinomycin D had no effect on the response to E2β, and eNOS abundance was similar in control and E2β-treated cells. E2β-stimulated eNOS activity was dependent on the influx of extracellular Ca2+, and was completely inhibited by the estrogen receptor (ER) antagonist ICI182,780. Messenger RNA and protein for the a isoform of ER (ERα) were evident in the H441 cells, and freshly isolated ovine airway epithelial cells also coexpressed eNOS and ERa. These findings indicate that estrogen acutely activates existing eNOS in H441 airway epithelial cells, through a process that involves the stimulation of epithelial ER and Ca2+ influx. This process may play a role in the hormonal modulation of airway function.

Original languageEnglish (US)
Pages (from-to)658-666
Number of pages9
JournalAmerican journal of respiratory cell and molecular biology
Issue number4
StatePublished - 1999

ASJC Scopus subject areas

  • Molecular Biology
  • Pulmonary and Respiratory Medicine
  • Clinical Biochemistry
  • Cell Biology


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