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Activation of nitric oxide synthesis in human endothelial cells by red clover extracts

Simoncini, Tommaso MD, PhD; Fornari, Letizia MD; Mannella, Paolo MD; Caruso, Antonella MD; Garibaldi, Silvia BSc; Baldacci, Chiara BSc; Genazzani, Andrea R. MD, PhD

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Objective: The unexpected findings of the Women's Health Initiative trial, where surrogate cardiovascular risk markers have failed to predict the cardiovascular performance of hormone therapy, showing no reduction of cardiovascular disease in postmenopausal women receiving hormonal preparations inducing a favorable lipid profile, raise the interest on how molecules with hormone-like activity used for the treatment of menopausal symptoms act on vascular cells. This is particularly important for estrogen-like compounds such as phytoestrogens, whose mechanisms of action may significantly differ from those of other estrogenic compounds.

Design: Because endothelial-derived nitric oxide (NO) is a key regulator of vascular tone and atherogenesis as well as a well-characterized estrogen-regulated molecule, we studied the regulation of NO synthesis in cultured human endothelial cells by phytoestrogens contained in red clover extracts.

Results: We show that red clover extracts activate NO synthesis in endothelial cells by recruiting transcriptional pathways but are not capable of inducing rapid NO synthesis through nongenomic mechanisms. During prolonged exposures, red clover extracts enhance the expression as well as the activity of endothelial nitric oxide synthase. These effects are mediated by a recruitment of estrogen receptor-β. Moreover, we show that red clover-derived isoflavones synergize with 17β-estradiol in increasing endothelial nitric oxide synthase activity and expression, therefore being devoid of antiestrogenic effects in human endothelial cells.

Conclusions: These results help to understand the mechanisms of action of phytoestrogens on the cardiovascular system and have relevant clinical implications.

In this study, red clover extracts activated NO syntheses in endothelial cells by recruiting transcriptional pathways but were not capable of inducing rapid NO synthesis through nongenomic mechanisms. These results help to understand the mechanisms of action of phytoestrogens on the cardiovascular system and have relevant clinical implications.

From Molecular and Cellular Gynecological Endocrinology Laboratory (MCGEL), Department of Reproductive Medicine and Child Development, Division of Obstetrics and Gynecology, University of Pisa, Pisa, Italy.

Received May 10, 2004; revised and accepted July 31, 2004.

Address correspondence to: Tommaso Simoncini, MD, PhD, Molecular and Cellular Gynecological Endocrinology Laboratory (MCGEL), Department of Reproductive Medicine and Child Development, Division of Obstetrics and Gynecology, University of Pisa, Via Roma, 57, 56100, Pisa, Italy. E-mail: t.simoncini@obgyn.med.unipi.it.

©2005The North American Menopause Society