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Molecular Pharmacology

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Research ArticleArticle

2-Methoxyestradiol, an Endogenous Estrogen Metabolite, Induces Apoptosis in Endothelial Cells and Inhibits Angiogenesis: Possible Role for Stress-Activated Protein Kinase Signaling Pathway and Fas Expression

Tian-Li Yue, Xinkang Wang, Calvert S. Louden, Shalley Gupta, Kodandaram Pillarisetti, Juan-Li Gu, Timothy K. Hart, Paul G. Lysko and Giora Z. Feuerstein
Molecular Pharmacology June 1997, 51 (6) 951-962; DOI: https://doi.org/10.1124/mol.51.6.951
Tian-Li Yue
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Xinkang Wang
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Calvert S. Louden
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Shalley Gupta
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Kodandaram Pillarisetti
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Juan-Li Gu
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Timothy K. Hart
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Paul G. Lysko
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Giora Z. Feuerstein
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Abstract

2-Methoxyestradiol (2-ME) is an endogenous metabolite of estradiol-17β and the oral contraceptive agent 17-ethylestradiol. 2-ME was recently reported to inhibit endothelial cell proliferation. The current study was undertaken to explore the mechanism of 2-ME effects on endothelial cells, especially whether 2-ME induces apoptosis, a prime mechanism in tissue remodeling and angiogenesis. Cultured bovine pulmonary artery endothelial cells (BPAEC) exposed to 2-ME showed morphological (including ultrastructural) features characteristic of apoptosis: cell shrinkage, cytoplasmic and nuclear condensation, and cell blebbing. 2-ME-induced apoptosis in BPAEC was a time- and concentration-dependent process (EC50 = 0.45 ± 0.09 μm, n = 8). Nucleosomal DNA fragmentation in BPAEC treated with 2-ME was identified by agarose gel electrophoresis (DNA ladder) as well as in situ nick end labeling. Under the same experimental conditions, estradiol-17β and two of its other metabolites, estriol and 2-methoxyestriol (≤10 μm), did not have an apoptotic effect on BPAEC. 2-ME activated stress-activated protein kinase (SAPK)/c-Jun amino-terminal protein kinase in BPAEC in a concentration-dependent manner. The activity of SAPK was increased by 170 ± 27% and 314 ± 22% over the basal level in the presence of 0.4 and 2 μm 2-ME (n = 3–6), respectively. The activation of SAPK was detected at 10 min, peaked at 20 min, and returned to basal levels at 60 min after exposure to 2-ME. Inhibition of SAPK/c-Jun amino-terminal protein kinase activation by basic fibroblast growth factor, insulin-like growth factor, or forskolin reduced 2-ME-induced apoptosis. Immunohistochemical analysis of BPAEC indicated that 2-ME up-regulated expression of both Fas and Bcl-2. In addition, 2-ME inhibited BPAEC migration (IC50 = 0.71 ± 0.11 μm, n = 4) and basic fibroblast growth factor-induced angiogenesis in the chick chorioallantoic membrane model. Taken together, these results suggest that promotion of endothelial cell apoptosis, thereby inhibiting endothelial cell proliferation and migration, may be a major mechanism by which 2-ME inhibits angiogenesis.

Footnotes

    • Received September 10, 1996.
    • Accepted February 26, 1997.
  • Send reprint requests to: Tian-Li Yue, Ph.D., Department of Cardiovascular Pharmacology, SmithKline Beecham Pharmaceuticals, P.O. Box 1539, UW2510, King of Prussia, PA 19406-0939. E-mail:tian-li-yue{at}sbphrd.com

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Molecular Pharmacology: 51 (6)
Molecular Pharmacology
Vol. 51, Issue 6
1 Jun 1997
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Research ArticleArticle

2-Methoxyestradiol, an Endogenous Estrogen Metabolite, Induces Apoptosis in Endothelial Cells and Inhibits Angiogenesis: Possible Role for Stress-Activated Protein Kinase Signaling Pathway and Fas Expression

Tian-Li Yue, Xinkang Wang, Calvert S. Louden, Shalley Gupta, Kodandaram Pillarisetti, Juan-Li Gu, Timothy K. Hart, Paul G. Lysko and Giora Z. Feuerstein
Molecular Pharmacology June 1, 1997, 51 (6) 951-962; DOI: https://doi.org/10.1124/mol.51.6.951

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Research ArticleArticle

2-Methoxyestradiol, an Endogenous Estrogen Metabolite, Induces Apoptosis in Endothelial Cells and Inhibits Angiogenesis: Possible Role for Stress-Activated Protein Kinase Signaling Pathway and Fas Expression

Tian-Li Yue, Xinkang Wang, Calvert S. Louden, Shalley Gupta, Kodandaram Pillarisetti, Juan-Li Gu, Timothy K. Hart, Paul G. Lysko and Giora Z. Feuerstein
Molecular Pharmacology June 1, 1997, 51 (6) 951-962; DOI: https://doi.org/10.1124/mol.51.6.951
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