Progestogens stimulate prostacyclin production by human endothelial cells

Abstract

Background: The effects of progestogens on endothelial physiology are poorly studied. Prostacyclin is a potent vasodilator synthesized by two isoforms of cyclooxygenase (COX) in endothelium. We examined the effects of two clinically used progestogens, progesterone and medroxyprogesterone acetate (MPA), on prostacyclin production by cultured human umbilical vein endothelial cells (HUVEC) and the possible role of progesterone receptors and both COX enzymes. Methods: Cells were exposed to 1-100nmol/l of either progesterone or MPA and prostacyclin production was measured in culture medium. Results: Both progestogens significantly increased prostacyclin release in a time- and dose-dependent manner, being higher than control after 24 h. Progesterone and MPA, both at 10 mmol/l, increased mRNA expression and protein content of both COX. All these effects were mediated through progesterone receptor activation, since they were abolished by treatment of cells with the progesterone receptor antagonist RU-486. Selective inhibitors of COX-1 and -2 (SC-560 and NS-398 respectively) reduced basal prostacyclin release, and eliminated increased production in response to progestogens. In combination with estradiol, progestogens had an additive effect without eliminatingestradiol-induced prostacyclin production. Conclusions: Our results support the hypothesis that progesterone and MPA increased HUVEC prostacyclin production in a progesterone receptor-dependent manner, by enhancing COX-1 and COX-2 expression and activities. © The Author 2005. Published by Oxford University Press on behalf of the European Society of Human Reproduction and Embryology. All rights reserved.