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Estrogen Receptor- Agonists Promote Angiogenesis in Human Myometrial Microvascular Endothelial Cells

Doris Sum Yue, BSc

John A. Katzenellenbogen, PhD

Peter A. W. Rogers, PhD

Centre for Women's Health Research, Monash University Department of Obstetrics and Gynaecology, Monash Medical Centre, Clayton, Victoria, Australia; Department of Chemistry, University of Illinois, Urbana, Illinois

Caroline E. Gargett, PhD

Centre for Women's Health Research, Monash University Department of Obstetrics and Gynaecology, Monash Medical Centre, Clayton, Victoria, Australia; Department of Chemistry, University of Illinois, Urbana, Illinois; caroline.gargett{at}med.monash.edu.au

Objective: The relative role of the two estrogen receptors, ER and ERß, in mediating angiogenic responses in adult human endothelium is unknown. The aim of this study was to determine whether novel ER-selective agonists, propyl pyrazole triol (PPT) and the tetrahydrochrysene (R,R-THC), up-regulate the expression of vascular endothelial growth factor receptor-2 (VEGFR-2),and promote VEGF-stimulated endothelial cell proliferation in primary cultures of adult female microvascular endothelial cells so-expressing endogenous ER and ERß.

Methods: Confluent primary cultures of microvascular endothelial cells isolated from human myometrium were incubated with 17ß-estradiol (1 and 10 nM), PPT (10 nM to 3 µM), or R,R-THC (10 nM to 3 µM) for 18 hours and VEGFR-2 expression measured by biotin-VEGF₁₆₅ binding and flow cytometry. Endothelial cell proliferation was assessed in microvascular endothelial cells after incubation with 17ß-estradiol (10 nM), PPT (100 nM), and R,R-THC (100 nM) for 6 days using a tetrazolium-based bioassay.

Results: Both PPT and R,R-THC increased VEGFR-2 expression on myometrial microvascular endothelial cells in a dose-dependent manner, reaching a maximum at 1 µM. Approximately 40% of myometrial microvascular endothelial cell isolates only express ERß and do not express ER, and in these neither PPT, R,R-THC, nor 17ß-estradiol increased VEGF binding. PPT- or R,R-THC-stimulated increase in VEGF binding was significantly different between ER⁺ and ER^- microvascular endothelial cell samples (P < .001 and P < .05, respectively). PPT, R,R-THC, and 17ß-estradiol significantly augmented VEGF-stimulated microvascular endothelial cell proliferation in ER⁺ (P < .05), but not in ER^- samples.

Conclusions: This angiogenic effect of 17ß-estradiol on adult female microvascular endothelial cells is mediated by ER, rather than ERß.

Key Words: ER • ER agonists • angiogenesis • human • microvascular endothelial cells • VEGF receptors • myometrium

Journal of the Society for Gynecologic Investigation, Vol. 11, No. 8, 529-535 (2004)
DOI: 10.1016/j.jsgi.2004.06.004


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