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(Arteriosclerosis, Thrombosis, and Vascular Biology. 2009;29:586.)
© 2009 American Heart Association, Inc.

Cell Biology/Signaling

Certain Progestins Prevent the Enhancing Effect of 17β-Estradiol on NO-Mediated Inhibition of Platelet Aggregation by Endothelial Cells

Murielle Zerr-Fouineau; Marie Jourdain; Caroline Boesch; Markus Hecker; Christian Bronner; Valérie B. Schini-Kerth

From the Département de Pharmacologie et Physico-Chimie (M.Z.-F., M.J., C.B., C.B., V.B.S.-K.), UMR CNRS 7175, Institut Gilbert Laustriat, Université Louis Pasteur Strasbourg I, Illkirch, France; and the Institute of Physiology and Pathophysiology (M.H.), University of Heidelberg, Germany.

Correspondence to Valérie B. Schini-Kerth, PhD, UMR CNRS 7175, Université Louis Pasteur Strasbourg I, Faculté de Pharmacie, 74, route du Rhin, B.P. 60024, F-67401 Illkirch, France. E-mail valerie.schini-kerth{at}pharma.u-strasbg.fr

Objectives— Estro-progestin treatments have been associated with an increased risk of thromboembolic events in postmenopausal women. This study examined whether progestins affect the stimulatory effect of estrogens on the endothelial formation of nitric oxide (NO), a potent antithrombotic factor.

Methods and Results— Experiments were performed with human endothelial cells. Endothelial NO synthase (eNOS) and GTP cyclohydrolase I (GTPCH I) mRNA expression was assessed by RT-PCR, eNOS protein by Western blotting, NO formation by electron spin resonance spectroscopy, and platelet aggregation by an aggregometer. Medroxyprogesterone acetate (MPA), progesterone, levonorgestrel, and nomegestrol acetate prevented the 17β-estradiol (17β-E)-induced expression of eNOS mRNA and protein. MPA and progesterone reduced the 17β-E-induced formation of NO and potentiation of the inhibitory effect of endothelial cells on platelet aggregation whereas levonorgestrel and nomegestrol acetate were without effect. Moreover, MPA and progesterone prevented the 17β-E-induced expression of GTPCH I mRNA. Mifepristone, a glucocorticoid and progesterone receptor antagonist, and L-sepiapterin prevented the inhibitory effect of MPA and progesterone on platelet aggregation.

Conclusions— Certain progestins, including MPA, attenuate the 17β-E-induced NO-mediated inhibition of platelet aggregation by endothelial cells through preventing both eNOS and GTPCH I expression most likely via activation of glucocorticoid receptors.

This study examined whether progestins antagonize the beneficial effect of 17β-estradiol on the endothelial formation of NO. The present findings indicate that certain progestins overcome the 17β-E-induced NO-mediated inhibition of platelet aggregation by endothelial cells, in part, by preventing the expression of eNOS and GTPCH I.

Key Words: 17β-estradiol • progestins • endothelial nitric oxide synthase • GTP cyclohydrolase • thrombosis

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Interference of Progestins With Endothelial Actions of Estrogens: A Matter of Glucocorticoid Action or Deprivation?

J.F. Arnal, P. Gourdy, and T. Simoncini
Arterioscler Thromb Vasc Biol 2009 29: 441-443. [Extract] [Full Text] [PDF]

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