Estrogen receptor mediates the nongenomic activation of endothelial nitric oxide synthase by estrogen

Zhong Chen, Ivan S. Yuhanna, Zoya Galcheva-Gargova, Richard H. Karas, Michael E. Mendelsohn, Philip W. Shaul

Research output: Contribution to journalArticle

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Abstract

Estrogen is an important vasoprotective molecule that causes the rapid dilation of blood vessels by activating endothelial nitric oxide synthase (eNOS) through an unknown mechanism. In studies of intact ovine endothelial cells, 17β-estradiol (E2) caused acute (five-minute) activation of eNOS that was unaffected by actinomycin D but was fully inhibited by concomitant acute treatment with specific estrogen receptor (ER) antagonists. Overexpression of the known transcription factor ERα led to marked enhancement of the acute response to E2, and this was blocked by ER antagonists, was specific to E2, and required the ERα hormone-binding domain. In addition, the acute response of eNOS to E2 was reconstituted in COS-7 cells cotransfected with wild-type ERα and eNOS, but not by transfection with eNOS alone. Furthermore, the inhibition of tyrosine kinases or mitogen-activated protein (MAP) kinase kinase prevented the activation of eNOS by E2, and E2 caused rapid ER-dependent activation of MAP kinase. These findings demonstrate that the short-term effects of estrogen central to cardiovascular physiology are mediated by ERα functioning in a novel, nongenomic manner to activate eNOS via MAP kinase-dependent mechanisms.

Original languageEnglish (US)
Pages (from-to)401-406
Number of pages6
JournalJournal of Clinical Investigation
Volume103
Issue number3
StatePublished - Feb 1999

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Nitric Oxide Synthase Type III
Estrogen Receptors
Estrogens
Mitogen-Activated Protein Kinases
Cardiovascular Physiological Phenomena
MAP Kinase Kinase Kinases
COS Cells
Dactinomycin
Protein-Tyrosine Kinases
Transfection
Blood Vessels
Dilatation
Estradiol
Sheep
Transcription Factors
Endothelial Cells
Hormones

ASJC Scopus subject areas

  • Medicine(all)

Cite this

Chen, Z., Yuhanna, I. S., Galcheva-Gargova, Z., Karas, R. H., Mendelsohn, M. E., & Shaul, P. W. (1999). Estrogen receptor mediates the nongenomic activation of endothelial nitric oxide synthase by estrogen. Journal of Clinical Investigation, 103(3), 401-406.

Estrogen receptor mediates the nongenomic activation of endothelial nitric oxide synthase by estrogen. / Chen, Zhong; Yuhanna, Ivan S.; Galcheva-Gargova, Zoya; Karas, Richard H.; Mendelsohn, Michael E.; Shaul, Philip W.

In: Journal of Clinical Investigation, Vol. 103, No. 3, 02.1999, p. 401-406.

Research output: Contribution to journalArticle

Chen, Z, Yuhanna, IS, Galcheva-Gargova, Z, Karas, RH, Mendelsohn, ME & Shaul, PW 1999, 'Estrogen receptor mediates the nongenomic activation of endothelial nitric oxide synthase by estrogen', Journal of Clinical Investigation, vol. 103, no. 3, pp. 401-406.
Chen, Zhong ; Yuhanna, Ivan S. ; Galcheva-Gargova, Zoya ; Karas, Richard H. ; Mendelsohn, Michael E. ; Shaul, Philip W. / Estrogen receptor mediates the nongenomic activation of endothelial nitric oxide synthase by estrogen. In: Journal of Clinical Investigation. 1999 ; Vol. 103, No. 3. pp. 401-406.
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