Progestins overcome inhibition of platelet aggregation by endothelial cells by down‐regulating endothelial NO synthase via glucocorticoid receptors

Abstract

Hormone replacement therapy with estroprogestin preparations is associated with an increased risk of venous and arterial thromboembolic events in postmenopausal women. This study examined whether progestins affect the formation of NO in endothelial cells, and, if so, to determine the underlying mechanism. Experiments were performed with human umbilical vein endothelial cells. Endothelial nitric oxide synthase (eNOS) expression was assessed by real-time polymerase chain reaction (PCR) and Western blot analysis, NO formation by electron spin resonance spectroscopy, nuclear translocation of the glucocorticoid receptor by immunofluorescence microscopy, and platelet aggregation by an aggregometer. Medroxyprogesterone acetate (MPA) and progesterone markedly decreased the eNOS mRNA and protein levels, whereas levonorgestrel and nomegestrol acetate had only small effects. This effect was associated with a decreased NO formation leading to a reduced ability of endothelial cells to prevent platelet aggregation and was prevented by knockdown of the glucocorticoid receptor using siRNA. MPA and progesterone, but not levonorgestrel and nomegestrol acetate, caused nuclear translocation of the glucocorticoid receptor. The present findings indicate that certain progestins, including MPA, reduce the antiaggregatory effect of endothelial cells by decreasing the expression of eNOS and the formation of NO in endothelial cells, an effect that is mediated via activation of glucocorticoid receptors.

Immunohistochemical Study of the Angiogenetic Network of VEGF, HIF1α, VEGFR-2 and Endothelial Nitric Oxide Synthase (eNOS) in Human Breast Cancer

“…The effect however of progesterone upon eNOS expression is not clear yet. Progesterone has been described to oppose to estrogen by down-regulating eNOS expression [39,40]. Such an observation might seem as discordance to our results.…”

Sex differences in vascular function: implication of endothelium-derived hyperpolarizing factor

“…While, in contrast, endothelial cell PGI 2 production is decreased by physiological doses of female sex hormones (17b-estradiol, progesterone or combined treatment; Berge et al 1990). In addition, certain progestins reduce the anti-aggregatory effect of endothelial cells by decreasing the expression of eNOS and the production of NO (Zerr-Fouineau et al 2007). All these negative effects of sex hormones on platelet function likely contribute to the increased risk of thrombosis shown in postmenopausal women using MHT.…”

Effects of Progesterone and Its Antagonist Mifepristone on Progesterone Receptor A Expression in Human Umbilical Vein Endothelial Cells

“…Studies on the effects of HT in postmenopausal women indicate procoagulant effects of gestagens and estrogens. To further study the effects of gestagens on hemostasis, Zerr-Fouineau et al [30] investigated whether progestins affect the formation of NO in endothelial cells and examined the underlying mechanism.…”