Published online before print January 17, 2008

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(American Journal of Pathology. 2008;172:534-544.)
© 2008 American Society for Investigative Pathology
DOI: 10.2353/ajpath.2008.061244

2-Methoxyestradiol Inhibits Hypoxia-Inducible Factor-1 and Suppresses Growth of Lesions in a Mouse Model of Endometriosis

Christian M. Becker^*, Nadine Rohwer, Tae Funakoshi^*, Thorsten Cramer, Wanja Bernhardt^¶, Amy Birsner^*, Judah Folkman^* and Robert J. D’Amato^*

From the Vascular Biology Program,^*Children’s Hospital Boston, Harvard Medical School, Boston, Massachusetts; the Department of Obstetrics and Gynaecology,Charité—Campus Benjamin Franklin, Berlin, Germany; the Nuffield Department of Obstetrics and Gynaecology,John Radcliffe Hospital, University of Oxford, United Kingdom; the Department of Gastroenterology,Charité—Campus Rudolf Virchow, Berlin, Germany; and the Department of Nephrology,^¶Friedrich-Alexander-Universität Erlangen-Nürnberg, Germany

Endometriosis, the presence of ectopic endometrial tissue outside the uterine cavity, is a common disease affecting women during their reproductive years. Current therapeutic success is often unsatisfactory because of limited insight into disease mechanisms. Nevertheless, angiogenesis plays an essential role in the pathogenesis of the disease, making it a potential novel target for therapy. In the current study, we demonstrate in an established mouse model of endometriosis that transient hypoxia in transplanted endometriosis-like lesions results in the up-regulation of hypoxia-inducible factor-1 (HIF-1), leading to the expression of vascular endothelial growth factor (VEGF), a key player in endometriosis-associated angiogenesis. Systemic treatment with the angiogenesis inhibitor 2-methoxyestradiol suppressed HIF-1 expression in vivo, resulting in a decreased downstream expression of HIF-1 target genes, such as for VEGF, phosphoglycerate kinase, and glucose transporter-1. 2-Methoxyestradiol also suppressed VEGF-induced vascular permeability, as demonstrated in a modified Miles assay. Finally, systemic treatment with 2-methoxyestradiol significantly inhibited the growth of endometriosis-like lesions in a dose-dependent manner. In conclusion, hypoxia appears to play an important role in the pathogenesis of endometriosis and endometriosis-associated angiogenesis, and the angiogenesis inhibitor 2-methoxyestradiol may be a potential candidate for systemic treatment in the future.

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